Review Article Association between Genetic Variants and Diabetes Mellitus in Iranian Populations: A Systematic Review of Observational Studies Mehrnoosh Khodaeian, 1 Samaneh Enayati, 1 Ozra Tabatabaei-Malazy, 2 and Mahsa M. Amoli 1 1 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran 2 Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran Correspondence should be addressed to Ozra Tabatabaei-Malazy; [email protected] and Mahsa M. Amoli; [email protected] Received 16 October 2014; Accepted 15 January 2015 Academic Editor: Aziz Ghahary Copyright © 2015 Mehrnoosh Khodaeian et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. Diabetes mellitus as the most prevalent metabolic disease is a multifactorial disease which is influenced by environmental and genetic factors. In this systematic review, we assessed the association between genetic variants and diabetes/its complications in studies with Iranian populations. Methods. Google Scholar, PubMed, Scopus, and Persian web databases were systematically searched up to January 2014. e search terms were “gene,” “polymorphism,” “diabetes,” and “diabetic complications”; nephropathy, retinopathy, neuropathy, foot ulcer, and CAD (coronary artery diseases); and Persian equivalents. Animal studies, letters to editor, and in vitro studies were excluded. Results. Out of overall 3029 eligible articles, 88 articles were included. We found significant association between CTLA-4, IL-18, VDR, TAP2, IL-12, and CD4 genes and T1DM, HNF and MODY, haptoglobin, paraoxonase, leptin, TCF7L2, calreticulin, ER, PPAR-2, CXCL5, calpain-10, IRS-1 and 2, GSTM1, KCNJ11, eNOS, VDR, INSR, ACE, apoA-I, apo E, adiponectin, PTPN1, CETP, AT1R, resistin, MMP-3, BChE K, AT2R, SUMO4, IL-10, VEGF, MTHFR, and GSTM1 with T2DM or its complications. Discussion. We found some controversial results due to heterogeneity in ethnicity and genetic background. We thought genome wide association studies on large number of samples will be helpful in identifying diabetes susceptible genes as an alternative to studying individual candidate genes in Iranian populations. 1. Introduction Diabetes mellitus, as the most prevalent metabolic disorder, is characterized by chronic hyperglycemia due to defect in insulin secretion by beta cells of Langerhans islets or resistance against insulin action [1–3]. More than 300 million people are suffering from diabetes mellitus all over the world and studies show that population aging, changes in lifestyle and improvement in detection techniques are most important factors in increasing the numbers of cases [4]. e prevalence of type 2 diabetes mellitus (T2DM) varies in different populations from less than 6% in most populations to more than 50% in Pima Indians [5]. In 2013 it was reported that in Middle East region about 35 million people suffered from diabetes. e prevalence of diabetes has been estimated as 382 million people throughout the world while nearly 176 million of them seem to be still undiagnosed. It is predicted that this prevalence reaches to 592 million by 2035. Diabetes mellitus can also cause complications in most of organs: heart, eye, kidney, and nervous system which has resulted in high economic cost and burden [6]. erefore, diagnosis of disease in early stages is very important. A systematic review showed that between years 1996 and 2004 the prevalence of type 2 diabetes in Iran was 24% and the risk was 1.7% greater in women. According to this report the prevalence of T2DM in Iran seems to be Hindawi Publishing Corporation Journal of Diabetes Research Volume 2015, Article ID 585917, 21 pages http://dx.doi.org/10.1155/2015/585917
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Review ArticleAssociation between Genetic Variants and DiabetesMellitus in Iranian Populations A Systematic Review ofObservational Studies
Mehrnoosh Khodaeian1 Samaneh Enayati1
Ozra Tabatabaei-Malazy2 and Mahsa M Amoli1
1Endocrinology and Metabolism Research Center Endocrinology and Metabolism Clinical Sciences InstituteTehran University of Medical Sciences Tehran Iran2Diabetes Research Center Endocrinology and Metabolism Clinical Sciences Institute Tehran University of Medical SciencesTehran Iran
Correspondence should be addressed to Ozra Tabatabaei-Malazy tabatabaeimlfarabitumsacir andMahsa M Amoli amolimmtumsacir
Received 16 October 2014 Accepted 15 January 2015
Academic Editor Aziz Ghahary
Copyright copy 2015 Mehrnoosh Khodaeian et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited
Introduction Diabetes mellitus as the most prevalent metabolic disease is a multifactorial disease which is influenced byenvironmental and genetic factors In this systematic review we assessed the association between genetic variants and diabetesitscomplications in studies with Iranian populations Methods Google Scholar PubMed Scopus and Persian web databases weresystematically searched up to January 2014The search terms were ldquogenerdquo ldquopolymorphismrdquo ldquodiabetesrdquo and ldquodiabetic complicationsrdquonephropathy retinopathy neuropathy foot ulcer and CAD (coronary artery diseases) and Persian equivalents Animal studiesletters to editor and in vitro studies were excluded ResultsOut of overall 3029 eligible articles 88 articles were included We foundsignificant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DM HNF120572 and MODY haptoglobinparaoxonase leptin TCF7L2 calreticulin ER120572 PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11 eNOS VDR INSRACE apoA-I apo E adiponectin PTPN1 CETP AT1R resistin MMP-3 BChE K AT2R SUMO4 IL-10 VEGF MTHFR andGSTM1 with T2DM or its complications Discussion We found some controversial results due to heterogeneity in ethnicity andgenetic backgroundWe thought genomewide association studies on large number of samples will be helpful in identifying diabetessusceptible genes as an alternative to studying individual candidate genes in Iranian populations
1 Introduction
Diabetes mellitus as the most prevalent metabolic disorderis characterized by chronic hyperglycemia due to defectin insulin secretion by beta cells of Langerhans islets orresistance against insulin action [1ndash3] More than 300millionpeople are suffering from diabetes mellitus all over theworld and studies show that population aging changes inlifestyle and improvement in detection techniques are mostimportant factors in increasing the numbers of cases [4]The prevalence of type 2 diabetes mellitus (T2DM) varies indifferent populations from less than 6 in most populationsto more than 50 in Pima Indians [5] In 2013 it was reported
that in Middle East region about 35 million people sufferedfrom diabetes The prevalence of diabetes has been estimatedas 382 million people throughout the world while nearly 176million of them seem to be still undiagnosed It is predictedthat this prevalence reaches to 592 million by 2035 Diabetesmellitus can also cause complications inmost of organs hearteye kidney and nervous system which has resulted in higheconomic cost and burden [6]Therefore diagnosis of diseasein early stages is very important
A systematic review showed that between years 1996and 2004 the prevalence of type 2 diabetes in Iran was24 and the risk was 17 greater in women Accordingto this report the prevalence of T2DM in Iran seems to be
Hindawi Publishing CorporationJournal of Diabetes ResearchVolume 2015 Article ID 585917 21 pageshttpdxdoiorg1011552015585917
2 Journal of Diabetes Research
highest amongst developing countries Previous reports ontotal urban population of Middle Eastern countries show theprevalence of T2DM as 34 in Sudan 20 in United ArabEmirates 85 in Bahrain and 121 in India [7]
DiabetesMellitus is categorized into the following groupsType 1 diabetes mellitus (T1DM) includes 5ndash10 of dia-
betic patients Cellular-mediated autoimmune destruction ofthe beta-cells of the pancreas results in T1DM It classicallyoccurs in juveniles and affected patients are dependent oninsulin injection in their lifetime and are very prone to ketosis[1 8 9]
T2DM includes 90ndash95 of patients with diabetesPatients with type 2 diabetes may be asymptomatic for longperiod of time Vascular complications such as nephropathyneuropathy retinopathy and cardiovascular disease maydevelop in these patients The impact of genetic componentappears to be stronger in T2DM compared to T1DM [1 8 9]
Gestational diabetes mellitus (GDM) is another typewhich is observed during pregnancy and the prevalence mayrange from 1 to 14 in all pregnancies [1 8 9]
MODY (maturity onset diabetes of young) is monogenicform of diabetes comprised of several types with variousfeatures which is consisting of 1ndash5 of patients diagnosed asT2DMTheonset of this type of diabetes is normally before 25years and its treatment is independent of insulin MODY inits different forms is inherited in autosomal dominant patternand presents as a result of mutation in transcription factorsgenes including HNF4120572 (hepatocyte nuclear factor) HNF1120573IPF1 (insulin promoter factor) and neuro-D1 [1 8 9]
There are also other types of diabetes which are con-sidered as secondary to other conditions for example anydamage to pancreas such as removal of pancreatic tissuetrauma pancreatic carcinoma and infection or underlyingdiseases including endocrine diseases that alter different hor-mones secretion which are antagonist to insulin resulting invarious clinical manifestations such as acromegaly Cushingrsquossyndrome pheochromocytoma glucagonoma somatostati-noma and diabetes Diabetes (or carbohydrate intolerance)is also found in increased frequency with a large numberof genetic syndromes such as Wolfram syndrome whichcauses diabetes mellitus diabetes insipidus and other neu-rodegenerative disorders MELAS (mitochondrial myopathyencephalopathy lactic acidosis and stroke) which is pre-sented with myopathy and encephalopathy caused by mito-chondrial mutation MIDD (maternally inherited diabetesand deafness) which causes diabetes and IPEX (immune dys-regulation polyendocrinopathy enteropathy and X-linkedsyndrome) which is X-linked and alters immune system andcauses multiple endocrine problems [1 8 9]
Diabetes mellitus is a multifactorial disease with bothenvironmental and genetic causes affecting its presence andincidence Genome wide association studies revealed thegenetic heterogeneity of diabetes and the fact that differencein ethnicity can result in different susceptible genes associatedwith diabetes [10 11] Studies on candidate genes related todiabetes revealed that several genes including PPRAG (per-oxisome proliferator-activates receptor gamma) IRS1 and2 (insulin receptor substrate) KCNJ11 (potassium inwardlyrectifying channel) and HNFA are associated with T2DM
Genome wide association studies (GWAS) showed that manygenes including Calpain 10 and TCF7L2 (transcription factor7-like 2) are associated with T2DM HHEX (hematopoiet-ically expressed homeobox) SLC30A8 (solute carrier fam-ily 30 (zinc transporter) member 8) CDK2AB (cyclin-dependent kinase inhibitor 2AB) and IG2BP2 (insulin-likegrowth factor 2) are other genes which have been shown to beassociated with T2DM based on GWAS Some of these genesare expressed in beta cells or involved in insulin secretionpathways [12 13] Other candidate genes in associationwith T2DM include PPAR120574 ACE (angiotensin convertingenzyme) MTHFR (methylene tetrahydrofolate reductase)FABP2 (fatty acid binding protein-2) and FTO (fat massand obesity associated gene) [14] GWAS was carried out inmany populations including Finnish French and AmericanCaucasians and showed different loci on most of the chro-mosomes associated with T2DM [15] Systematic review andmeta-analysis studies also confirmed the association of somegenes such as PGC-1120572 (peroxisome proliferator-activatedreceptor gamma coactivator-1120572) and adiponectin with T2DM[16 17] The genetic loci associated with T1DM have alsobeen examined For example insulin (INS) gene VNTRs(variable number of tandem repeats) with a protective effectis a variants related to T1DM In addition PTPN22 (proteintyrosin phosphatase) CTLA4 and IL2RA genes have alsobeen shown as candidates for T1DM due to their role in T-cell signaling Studies have also confirmed the associationbetween IFIH1 CYP27B1 and CLEC16 which are importantin immune system and T1DM [18]
There is no inclusive information for genetic associationstudies of diabetes in Middle Eastern population includingIranian population In order to make a comprehensiveapproach we aimed to collectively investigate and gather datafor association between genetic variants and type 2 diabetesin Iranian population in a systematic review study
2 Research Design and Methods
This study is reported according to PRISMA (preferredreporting items for systematic reviews and meta-analyses)guideline [19]
21 Data Sources and Searches We systematically searchedinternational web databases Google Scholar PubMed Sco-pus and Persian web databases IranMedex and Magiran toinvestigate the association of genetic variants with diabetesand its complications in Iranian population up to January2014 The search terms were ldquogenerdquo ldquopolymorphismrdquo ldquodia-betesrdquo ldquodiabetesrsquo complicationsrdquo nephropathy retinopathyneuropathy foot ulcer and CAD (coronary artery disease)and their MeSH terms and Persian equivalents with diabetesAt least three emails were sent to the corresponding authorof articles which were not accessible as full text or hadinsufficient data Duplicate articles and multiple publicationsfrom the same population were excluded and the mostrelevant data were used for the investigation The referencesof all selected articles were investigated
22 Study Selection We included all observational popula-tion-based studies ge100 sample size which were conducted
Journal of Diabetes Research 3
Iden
tifica
tion
Records identified through
Scre
enin
gEl
igib
ility
Inclu
ded
Eligible full texts records
Included records to systematic
database searching (n = 3029)
Records excluded by title (n = 2734)
- Excluded due to duplicatepublication (n = 106)
(n = 104)
review (n = 88)
Records excluded by full text (n = 16)
- Excluded due to data from the samepopulation (n = 13)
- Excluded due to not measuredrelevant outcomes (n = 3)
- Google scholar (n = 2000)
- PubMed (n = 300)
- Scopus (n = 557)
- Persian web databases (n = 172)
- Excluded by abstract (n = 85)
Figure 1 Flow diagram of study selection process
as case-control cohort or cross sectional According toWHO criteria diabetes mellitus was defined as FBS ge7mmolL (126mgdL) or 2 h plasma glucose ge111mmolL(200mgdL) [20] In addition we excluded animal studiesclinical trials short communications letters to editor disser-tations in vitro studies review articles and population-basedstudies conducted in pregnant women Two researchers SEand MKH independently reviewed title abstract and fulltext of each article to assess the eligible articles according toinclusion and exclusion criteria Inclusion and exclusion ofarticles were supervised by a third reviewer (OTM) in case ofconflicts There was no limitation for language
23 Data Extraction and Quality Assessment The follow-ing data were extracted and presented in an excel sheetauthor(s) year genes and SNPs patientsrsquo characteristics(sample size age and sex) city study design genotypingmethod and significant association Six selected items fromthe STROBE (strengthening the reporting of observationalstudies in epidemiology) checklist [21] was used for qualityassessment of the included studies and assessed separatelyfor each included article The below items were considered(a) clearly define the outcome and association between genevariants and diabetes (b) give the eligibility criteria (c)present key elements of study design (d) report numbers orsignificancenonsignificance statistically of outcome events(e) give characteristics of study participants and (f) describethe locations and relevant dates All studies with quality scorege3 were considered as high quality study and included in oursystematic review
24 Data Synthesis and Analysis Due to heterogeneity ingenotyping techniques and also differences in genetic variantsstudied in assessed included articles performing a meta-analysis was impossible
3 Results
31 Search Results A summary of the literature reviewprocess performed in this study is presented in a flow chartin Figure 1 In final step 88 eligible studies were includedin this study and assessed due to the inclusionexclusioncriteria [22ndash109] Table 1 shows the summary of each includedinvestigation
32 Studies Characteristics Overall 27396 diabetics andhealthy subjects were studied in this systematic review Allof the subjects were recruited from total urban populationT2DMwas themost investigated type of diabetes (42 studies)[22ndash75] Among diabetes complications diabetic nephropa-thy and CAD were the most examined respectively [80ndash105] Twelve studies were carried out on T1DM [22ndash33]The least investigated complication was diabetic foot ulcerwhich was assessed only in one study [109] Retinopathyand insulin resistance were also among the least investigatedcomplications including 3 and 4 studies respectively [76ndash79 106ndash108] Only one study assessed MODY in our review[34] All of the studies were performed on both gendersexcept for one which was performed on males [45]
Details of the included studies are described as below
4 Journal of Diabetes Research
Table1Ch
aracteris
ticso
fincludedarticlesinsyste
maticreview
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
T1DM
andcomplications
Ahm
adietal2013
[22]
CTLA
-4+49AG
60T1DM56T2
DMand
107
healthymale(M)female(F)
Kurdistan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAG
carriersandT1DM
(P=001)
Karamizadeh
etal2013
[23]
(i)Oste
opon
tinrs11
26772
(ii)Integrin1205724rs1449263
CD44
rs8193
87T1DM
and86
healthy
lt20
yrM
FSh
iraz
Case
control
PCR-RF
LPNon
significance
Rahb
ani-N
abar
etal2013
[24]
IL-18minus137C
G104T1DM
and92
healthy
9ndash32
yrM
FTabriz
Case
control
SS-PCR
Positives
ignificantassociatio
nbetweenGGcarriersandT1DM
(P=0037)
Bonakd
aran
etal2012
[25]
(i)VDRFokI
(FFFfff
)(ii)B
smI(BB
Bbbb)
ApaI
(AA
Aaaa)
(iii)TaqI
(TTTttt)
69T1DM
and45
healthy
lt35
yrM
FMashh
adCa
secontrol
PCR-RF
LP
Positives
ignificantassociatio
nbetweenAa(
P=0003)FF
(P=0008)and
Bb(P
=0014)
carrierswith
T1DMsignificant
associationbetweenffgeno
type
andhisto
ryof
ketoacidosis
(P=004)
Moh
ammadnejadetal2012
[26]
(i)VDRTaqI
(TTTttt)
(ii)V
DR
FokIB
smIAp
aI87
T1DM
and100healthy
17ndash38y
rMF
Mashh
adCa
secontrol
PCR-RF
LP
(i)Negatives
ignificant
associationbetweenTT
carriers
andT1DM
(P=0007)
(ii)N
onsig
nificance
association
betweenotherc
arrie
rsof
VDR
andT1DM
Afsharietal2011[27]
(i)TA
P2Ile379Va
l(ii)T
AP2
Stop687Gln
(iii)TA
P2Ala565Th
rArg651Cy
sAla665Th
r
87T1DM
and104healthy
lt30
yrM
FMashh
adCa
secontrol
ARM
S-PC
R
(i)Sign
ificant
association
betweenIle
379V
alandT1DM
(P=0001)
(ii)S
ignificantassociatio
nbetweenStop
687G
lnandT1DM
(P=0013)
(iii)Non
significantassociatio
nbetweenotherc
arrie
rsof
TAP2
andT1DM
Massoud
etal2009
[28]
(i)IL-18minus137C
G(ii)IL-18minus607A
C75
T1DM
and88
healthy
lt30
yrM
FTehran
Case
control
PCR-SSP
(i)Po
sitives
ignificantassociatio
nbetweenGGcarriersandT1DM
(P=000
01)
(ii)S
ignificantassociatio
nbetweenCC
geno
type
with
T1DM
(P=000
01)
(iii)Non
significance
association
betweenotherc
arrie
rsof
IL-18
andT1DM
Journal of Diabetes Research 5
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Masou
detal2007
[29]
TGF120573
+915C
G75
T1DM
and88
healthy
lt30
yrM
FTehran
Case
control
PCR-SSP
Non
significance
Masou
detal2007
[30]
IL-12+1188A
C75
T1DM
and88
healthy
lt30
yrM
FTehran
Case
control
PCR-SSP
Sign
ificant
associationbetween
AAandAC
geno
type
andT1DM
(P=0035)
Mojtahedi
etal2006
[31]
IL-18minus607A
C
minus137C
G112T1DM
and194no
n-DM
lt15
andgt15yrM
FSh
iraz
Case
control
PCR-SSP
minus137C
Candminus607A
Aminus137C
Csig
nificantassociatio
nwith
T1DM
inon
setgt
15yr
(P=0027)
Mojtahedi
etal2005
[32]
CTLA
-4+49AG
109T1DM
and331h
ealth
y0ndash
37yrM
FSh
iraz
Case
control
PCR-SSP
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenAG
carriersandT1DM
(P=000)
(ii)N
egatives
ignificant
associationbetweenAAcarriers
andT1DM
(P=000)
Zamanietal2005
[33]
CD4A2
ndashA9
92T1DM
and108healthy
gt35
yrM
FTehran
Case
control
PCR
Negatives
ignificantassociatio
nbetweenA3alleleandT1DM
(P=0025)
Positives
ignificantassociatio
nbetweenA5alleleandT1DM
(P=0001)
MODY
Tagh
avietal2009
[34]
HNF120572
Val255M
et30
MODY21
relativ
esand
50healthy25ndash35y
rMF
Mashh
adCa
secontrol
PCR-FL
Psequ
encing
Them
utationwas
foun
din
patie
ntsa
ndrelatives
butn
otin
controls
T2DM
andcomplications
Ahm
adietal2013
[22]
CTLA
-4+49AG
Said
above
Said
above
Said
above
Said
above
Non
significance
Amiri
etal2013
[35]
Haptoglob
in1-
12-12-2
134T2
DM
with
MVC
s71
T2DM
with
outM
VCs
46ndash72y
rMF
Sari
Case
control
PCR
Hp2-2
high
lysig
nificantfor
T2DM
(P=005)
And
alib
etal2013
[36]
Paraoxon
ase2
Ser311Cys
100T2
DM
and100healthy
51yrM
FIsfahan
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
CysCy
sand
CysSerc
arrie
rsand
negativ
esignificantassociatio
nof
SerSerc
arrie
rswith
T2DM
(Plt005)
Kohanetal2013
[37]
LeptinG
-2548A
100T2
DM
and100healthy
44ndash6
6yrMF
Arsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersandT2
DM
(P=000
4)
Alamietal2013
[38]
TCF7L2
rs7903146
(CT)
233T
2DM
and233controls
gt40
yrM
FGorgan
Case
control
PCR-RF
LPCC
andCT
geno
typessignificant
differenceb
etweenT2
DM
and
controls(P
=0045)
Mahmazietal2013
[39]
Calre
ticulin
120T2
DM
and530controls
43ndash6
6yrMF
Zanjan
Case
control
PCR-SC
A9b
pdeletio
nof
397ndash399codo
nsGgtTmutationatIV
SII-142in
T2DM
notincontrols
6 Journal of Diabetes ResearchTa
ble1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Moh
ammadietal2013
[40]
(i)ER120572PvuII(PPPp
pp)
(ii)E
R120572XbaI(XX
Xxxx)
174T2
DM
and174ND
35ndash6
5yrMF
Jahrom
Case
control
PCR-RF
LP
(i)Sign
ificant
associationwith
T2DM
(P=0014)
TC(P
=0007)and
TG(119875=0005)fem
alec
arrie
rs(ii)S
ignificantassociatio
nwith
T2DM
(119875=0002)TC
(119875=0003)andTG
(119875=0009)
femalec
arrie
rs
Motavallianetal2013
[41]
PPAR-1205742Pro12A
la100T2
DM
and100healthy
51yrM
FIsfahan
Case
control
PCR-RF
LP
Negatives
ignificantassociatio
nbetweenAlaA
lacarriers
(119875lt0001)a
ndpo
sitive
significantassociatio
nbetween
AlaPro
carrierswith
T2DM
(119875lt0001)
Sepahi
etal2013
[42]
HNF-1120572Ala98Va
lGLP
-1RTh
r149Met
100T2
DM
and50
healthy
controlsle35
andgt35
yrM
FMashh
adCa
secontrol
PCR-RF
LPNon
significance
Sheikh
haetal2013
[43]
APO
A1M
SP-I
200T2
DM
and200healthy
418yrM
FYazd
Case
control
PCR-RF
LPNon
significance
Yagh
oubietal2013
[44]
CXCL
5minus156GgtC
100T2
DM54y
rand
100healthy
56yrM
FArdabil
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GCcarriers(119875=0006)a
ndnegativ
esignificantassociatio
nof
GGcarrierswith
T2DM
(P=001)
Bahreini
etal2012
[45]
Calpain-10SNP4
3(AG)
102T2
DM
and100healthy
40ndash70y
rM
EastAzerbayjan
Case
control
PCR-RF
LPGallelea
srisk
factor
ofT2
DM
(P=0037)
Derakhshanetal2012
[46]
SDF-1120573G
801A
200T2
DM
and200healthy
40yrM
FRa
fsanjan
Case
control
PCR-RF
LPNon
significance
Haghani
etal2012
[47]
(i)IRS-1G
972R
(ii)IRS
-2G
1057D
336T2
DM
and341h
ealth
y44
ndash63y
rMF
Ilam
andKe
rmanshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
GR(P
=0001)andRR
(119875=00001)carrie
rswith
T2DM
(ii)P
ositive
significant
associationbetweenGDcarriers
andT2
DM
(P=0016)
Alamietal2012
[48]
TCF7L2
rs12
255372
(GT)
236T2
DM
and255healthy
gt37
yrM
FGorgan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersandT2
DM
(P=0014)
Meshk
anietal2012
[49]
(i)ER120572PvuII(PPPp
pp)
(ii)E
R120572XbaI(XX
Xxxx)
155T2
DM
and377controls
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
pooled
Pp+pp
malec
arrie
rs(P
=0001)with
T2DM
(ii)P
ositive
significant
associationof
pooled
XX+
xxmalec
arrie
rs(P
=0026)
with
T2DM
Journal of Diabetes Research 7
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Moasser
etal2012
[50]
GST
M1p
resentnull
GST
T1presentnull
GST
P1Ile105Va
l
171T
2DM
and169healthy
25ndash6
5yrMF
Shira
zCa
secontrol
PCR-RF
LP
GST
M1-n
ull(P=0016)
and
interactionof
GST
M-nullG
STT1-null
(119875=0022)significant
associationwith
T2DM
Moh
addese
tal2012
[51]
SLC3
0A8Arg325Trp
125T2
DM
and125controls
40ndash70y
rMF
Azarbayjan
Case
control
PCR-RF
LPNon
significance
Oladi
etal2012
[52]
Glucokinaseminus30GA
542subjects
18ndash6
5yrMF
Mashh
adCr
osssectio
nal
PCR-RF
LPNon
significance
Palizbanetal2012
[53]
TCF7L2
rs7903146
(CT)
110T2
DM
and80
healthy
46ndash6
7yrMF
Isfahan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersandT2
DM
(P=0008)
Tabatabaei-M
alazyetal2012
[54]
ApoE
E3-E3
E2-E3
E4-E3
156T2
DM
and155healthy
25ndash6
5MF
Tehran
Case
control
PCR-RF
LPNon
significance
Ghasemietal2012
[55]
KCNJ11
E23K
358T2
DM
and388healthy
41ndash6
9yrMF
Rasht
Case
control
Realtim
ePCR
Positives
ignificantassociatio
nbetweenKK
carriersandob
ese
T2DM
(P=0037)
Ranjbare
tal2011[56]
Adipon
ectin
+45TG
minus113
91GA
244T2
DM
and99
healthy
37ndash6
5yrMF
Rafsanjan
Case
control
PCR-RF
LPNon
significant
Mehrab-Moh
seni
etal2011[57]
eNOSVNTR
intro
n4ab
220T2
DM
and96
healthy
53plusmn15yrM
FRa
fsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenaa
orab
carriersand
T2DM
(P=002)
Nosratabadi
etal2011[58]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DM
and100healthy
40yrM
FRa
fsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandT2
DM
(Plt0001)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandT2
DM
Saberietal2011[59]
ENPP
1K121Q
155T2
DM
and377healthy
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LPNon
significance
Fallahetal2010
[60]
SUMO4Met55Va
l(16
3AG
)50
T2DM
and50
healthy
25ndash4
5yrMF
Tehran
Case
control
PCR-RF
LPNon
significance
Heidarietal2010
[61]
UCP
2minus866G
A75
T2DM75NDob
esea
nd75
NDno
nobese35ndash76
yrM
FTehran
Case
control
PCR-RF
LPNon
significance
Nazem
etal2010
[62]
5HTT
LPRSSSLLL
90T2
DM
and90
healthy
54ndash6
6yrMF
Shira
zCa
secontrol
PCR
Non
significance
Bazzaz
etal2010
[63]
MTH
FRC677T
401T
2DM74NDob
esea
nd207
NDno
nobese30ndash
63yrM
FTehran
Case
control
PCR-RF
LPNon
significance
Emam
gholipou
retal2009
[64]
resistin
minus420C
G47
T2DM
and66
healthy
58plusmn9y
rMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandT2
DM
(P=000
9)
Hasani-R
anjbar
etal2009
[65]
CXCL
5minus156G
C230T2
DM
and120healthy
40ndash6
3yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGCor
CCcarriersand
T2DM
(P=000
4)
8 Journal of Diabetes ResearchTa
ble1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
KazemiA
rababadi
etal2009
[66]
IL-4minus590C
TIFN-120574+874T
A160T2
DM
and160healthy
38plusmn9y
rMF
Rafsanjan
Case
control
PCR-RF
LPARM
S-PC
RNon
significance
Arababadi
etal2009
[67]
CCR5
12057532mutation
200T2
DM
and300healthy
40plusmn9y
rMF
Rafsanjan
Case
control
Gap-PCR
Non
significance
Kazemietal2009
[68]
INSR
128T2
DMgt
40yrM
FTehran
Case
control
PCR
CSGE
sequ
encing
Follo
wingmutations
werefou
ndon
lyin
T2DM
511CgtA514Tgt
G586and
628TgtAon
exon
2694GgtCand680GgtAon
exon
31627AgtTon
exon
8ATgtTG
onintro
n9
2007Cgt
CTon
exon
92595Cgt
CTand2669GgtCGon
exon
132706
and2717Cgt
G2752CgtT
2753Cgt
Gonexon
143471Tgt
Aand3516Tgt
Gon
exon
19
Mirz
aeietal2009
[69]
PPAR120574
2Pro12A
la78
norm
al78ob
ese78
T2DM
and78
obeseT
2DM25ndash64
yr
MF
Tehran
Crosssectio
nal
PCR-RF
LPNon
significance
Nikzamiretal2008
[70]
ACEinsertion(I)
deletion(D
)170T2
DM
and144healthyMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(P=002)
Sharifi
etal2008
[71]
HFE
H63D
C282Y
101T
2DM
and101h
ealth
y55plusmn11yrM
FZa
njan
Case
control
PCR
Non
significance
Besharatietal2007
[72]
(i)Ap
oA-IG
-75A
(ii)A
poA-
IC+8
3T215subjects26ndash
64yrM
FTehran
Crosssectio
nal
PCR-RF
LP
(i)Non
significantassociatio
nbetweenG-75A
carriersand
T2DM
(ii)P
ositive
significant
associationbetweenCT
carriers
andT2
DM
(P=0028)
Hasani-R
anjbar
etal2007
[73]
Adipon
ectin
+45TG
80T2
DM
obese72
T2DM
nono
beseand
70healthy
25ndash6
4yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersand
nono
bese
T2DM
(P=004)
Meshk
anietal2007
[74]
PTPN
1minus51delA
minus451AgtGminus467TgtC
minus1023Cgt
Aminus1045GgtAminus1286
3bpdel
ACAminus1291
9bpdel
CTAG
ACTA
A
174T2
DM
and412healthy
23ndash79MF
Tehran
Case
control
PCR
sequ
encing
PCR-RF
LPNon
significance
Meshk
anietal2007
[75]
PPAR120574
Pro12Ala
412T2
DM
and284healthy
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LPNegatives
ignificantassociatio
nbetweenProAlaor
AlaA
lacarriersandT2
DM
(P=0003)
Journal of Diabetes Research 9
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
T2DM
patie
ntsa
ndinsulin
resistance
Nam
varanetal2012
[76]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin
receptor-2+795G
A
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTG
carriersandT2
DM
(P=0032)
(ii)N
onsig
nificantassociatio
nbetween+7
94GA
carriersand
insulin
resistance
Nam
varanetal2011[77]
PPAR120574
Pro12Ala
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
Realtim
ePCR
Positives
ignificantassociatio
nbetweenAlaallelecarriersand
T2DM
(P=0036)
Hossein-nezhadetal2009
[78]
VDRFokI
(FFFfff
)105T2
DM55plusmn10yrM
FTehran
Case
serie
sPC
R-RF
LPPo
sitives
ignificantassociatio
nbetweenffcarriersandinsulin
resistanceind
ex(P
=002)
Moo
sapo
oretal2007
[79]
PTPN
1148insG
71T2
DM
and264ND
20ndash80y
rMF
Tehran
Case
control
PCR-RF
LP
Negatives
ignificantassociatio
nbetween148insGcarriersand
insulin
resistanceind
ex(119875=0041)
T2DM
patie
ntsa
ndheartd
iseases
Bayatm
akoo
etal2013
[80]
Paraoxon
ase116
3TA
(L55M)
105CA
DD
Mand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPNon
significance
Bayatm
akoo
etal2012
[81]
Paraoxon
ase1575Ggt
A(Q
192R
)105DMCADand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenRR
carriersand
CADD
M(Plt005)
Estegh
amatietal2012
[82]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin+276G
T114
CADD
Mand127DM
42ndash71yrMF
Tehran
Case
control
PCR-RF
LP
(i)Negatives
ignificant
associationbetween45TT
carriersandCA
D(P
=0033)
(ii)P
ositive
significant
associationbetween276G
GcarriersandCA
D(P
=0023)
Rahimietal2012
[83]
eNOSG8
94T
CETP
B1
102CA
DD
M105
CADN
D101
DMand
92ND45ndash66
yrM
FKe
rmanshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
concom
itant
presence
ofNOS3
TalleleandCE
PTB1
allelewith
T2DM
(P=000
4)andCA
D(119875=0002)
Assalietal2011[84]
AT1RA116
6C145CA
DD
Mand164CA
D
lt50
andge50
yrM
FMashh
adCa
secontrol
PCR-RF
LPPo
sitives
ignificantassociatio
nof
ACandCC
carrierswith
DM
(119875=001)
Emam
gholipou
retal2009
[85]
Resistin
minus420C
G113CA
Dwith
andwith
outD
M
58plusmn9yrM
FTehran
Crosssectio
nal
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDM
(119875=0009)
10 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Fallahetal2010
[86]
MMP-3minus1612
5A6A
305CA
DD
Mand313DM
61plusmn9yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetween6A
6AcarriersandCA
S(P
=0008)
Vaisi-Raygani
etal2010
[87]
BChE
KG1
615A
APO
EE2
E3E4
118DM162
CADN
D172
DMCADand
179healthy
42ndash6
8yrMF
Kerm
anshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GAA
Aand
E4carrierswith
CADandDM
(Plt005)
Positives
ignificantassociatio
nof
BChE
KAp
oE4carrierswith
CADand
DM
(Plt005)
Sign
ificant
associationof
BChE
KAp
oE4with
lipid
profi
le(119875lt005)
Rahimietal2009
[88]
Factor
VLeidenG
1691A
Prothrom
binG2
0210A
MTH
FRC677T
65CA
DD
M52CA
DN
Dand
59healthy46
064y
rMF
Kerm
anshah
Case
control
PCR-RF
LPNon
significance
Nakhjavanietal2007
[89]
ACEID
82DM
with
hypertensio
nand87
DM
with
outh
ypertension
49ndash6
3yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
hypertensio
n(P
=0026)
Vaisi-Raygani
etal2007
[90]
Apolipop
roteinE2E3
E4
152CA
DD
M262
CADN
D
and300healthy35ndash73y
rMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nof
E2andE4
allelec
arrie
rswith
CAD(Plt0001)
T2DM
patie
ntsa
ndneph
ropathy
Rahimietal2013
[91]
eNOS4abG
894T
63T2
DMm
icroalbu
minuria
57T2
DMm
acroalbu
minuria
52T2
DMnormoalbum
inuria
121D
Nand
101h
ealth
y45ndash6
6yrMF
Kerm
anshah
Case
control
PCR
PCR-RF
LP
Positives
ignificantassociatio
nof
4aor
894T
allelecarriersand
macro-(P=001)o
rmicroalbu
minuria(P
=002)
Rahimietal2013
[92]
AT2R
minus1332GA
28T2
DMm
icroalbu
minuria
22T2
DMm
acroalbu
minuria
20T2
DMnormoalbum
inuria
and112healthy43ndash6
3yrMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(P
=0016)
Shahsavare
tal2013
[93]
SUMO4163A
G(M
55V)
50T2
DD
Nand50
T2DM
non-DN25ndash45
yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(Plt005)
Arababadi
etal2012
[94]
IL-10minus592C
A100T2
DMnon
-DN100
T2DMD
Nand100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDN
(119875=0001)
Journal of Diabetes Research 11
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2012
[95]
VEG
F+4
05G
C255T2
DMm
icroalbu
minuria
and235T2
DMnon
albu
minuric
50ndash6
7yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersand
albu
minuria(P
=0002)
Rahimietal2012
[96]
MTH
FRA1298C
C677T
ACEID
72T2
DMM
icAlb
68T2
DMM
acAlband72
T2DMnon
-DN46ndash
65yrM
FKe
rmanshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nof
ACED677T(P
=0035)
and
ACED12
98C(P
=0012)
carrierswith
macroalbu
minuria
Rahimietal2012
[97]
eNOSG8
94T
ACEID
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nbetweenAC
EDcarriersand
macroalbu
minuria(P
=0035)
Feleh
garietal2011[98]
ACEID
68T2
DMm
acroalbu
minuria
and72
T2Dmnormoalbum
inuria
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR
Non
significance
Jafarietal2011[99]
eNOSG8
94T
MTH
FRC677TA
1298C
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
eNOST1298
CandeN
OS
T677Tcarrierswith
macroalbu
minuria(Plt005)
(ii)S
ignificantassociatio
nof
eNOSGT+
TTcarrierswith
lipid
profi
le(Plt005)
Rahimietal2011[100]
ACEID
Factor
VLeidenG
1691A
217mean55both
Kerm
anshah
Case
control
PCR
PCR-RF
LPNon
significance
Arababadi2010[101]
IL-4minus590C
T100T2
DMD
Nand150healthy
33ndash4
7yrMF
Rafsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenCT
carriersandDN
(119875lt0001)
Nosratabadi
etal2010
[102]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DMnon
-DN100
T2DMD
Nand
100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandDN
(119875=0012)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandDN
Rahimietal2010
[103]
MTH
FRC677TA
1298C
72T2
DMm
icrolbum
iunira
68T2
DMm
acroalbu
minuria
and72
T2DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
677T1298C
and677T
1298C
carrierswith
macroalbu
minoria
(Plt0001)
(ii)P
ositive
significant
associationof
CT+T
Tand
677T
1298Ccarrierswith
microalbu
minuria(Plt0001)
12 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2009
[104]
ACEID
129T
2DMm
icrolbum
iunira
48T2
DMm
acroalbu
minuria
and145T
2DMnormoalbum
inuria
594plusmn85y
rMF
Tehran
Crosssectio
nal
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
progressionof
albu
minuria
(119875lt001)b
utno
tits
developm
ent
Nikzamiretal2006
[105]
ACEID
85T2
DMD
N85T2
DMnon
-DN
and91
healthy37ndash6
7yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(119875=0006)b
utno
tDN
T2DM
patie
ntsa
ndretin
opathy
Abbasietal2013
[106]
GST
M1n
ullp
ositive
80DRand80
healthy
30ndash70y
rMF
Rasht
Case
control
ARM
S-PC
RNullgenotypes
ignificant
association
Plt005
Dadbinp
oure
tal2013
[107]
(i)GST
M1n
ullp
ositive
(ii)G
STT1nullp
ositive
57DRand58
non-DR
35ndash6
5yrMF
Yazd
Case
control
Multip
lexPC
R
(i)Nullgenotypeo
fGST
M1o
rGST
T1sig
nificantassociatio
n(119875=004)
(ii)N
onsig
nificantassociatio
nof
GST
T1nu
llcarrierswith
DR
Fegh
hietal2011[108]
VEG
F+4
05G
C119
diabeticsw
ithPD
Rand279
diabeticsw
ithNPD
R47ndash6
6yrMF
Ahvaz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersanddiabetic
retin
opathy
(P=0005)
T2DM
patie
ntsa
ndfoot
ulcer
Amolietal2011[109]
(i)VEG
Fminus7C
T(ii)V
EGFminus2578CA
247T2
DM
with
DFU
241
T2DM
with
outD
FUand
98healthy
43ndash6
4MF
Tehran
Case
control
ARM
S-PC
R
(i)Non
significantassociatio
nof
minus7C
Tcarrierswith
DFU
(ii)P
ositive
significant
associationbetweenAAcarriers
andDFU
(P=003)
SNPsin
glenu
cleotid
epo
lymorph
ismT
1DMtype1d
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4T2
DMtype2diabetes
mellitusP
CRp
olym
erasechainreactio
nRF
LPrestrictio
nfragmentlengthpo
lymorph
ismILinterle
ukinSS-PC
Rsequ
ence
specificP
CRV
DR
vitamin
DreceptorT
AP2
transpo
rter
2AT
P-bind
ingcassetteA
RMS-PC
Ram
plificatio
nrefractory
mutationsyste
mPC
RPC
R-SSPPC
Rsin
glespecificprim
erT
GF120573
transform
inggrow
thfactor120573D
Md
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4
MODY
maturity
onsetd
iabeteso
fthe
youn
gHNF-
1120572h
epatocytenu
clear
factor
1120572M
VCm
icrovascular
complicationsT
CF7L
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tionfactor
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e2PC
R-SSCA
PCR
singlestr
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lymorph
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ER120572estr
ogen
receptor120572N
D
nond
iabeticsTC
totalcholesterolTG
trig
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esP
PAR-1205742peroxisomep
roliferator-activates
receptor120574G
LP-1R
glucagon
-like
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1receptorAPO
apo
lipop
roteinC
XCL5chemokineC
-X-C
motifligand
5SD
F-1120573stro
malderiv
edfactor-1120573IRS
1amp2insulin
receptor
substrate1amp
2GSTglutathione-S-tr
ansfe
raseSLC
30A8solublecarrier3
0A8KC
NJPo
tassium
inwardly-rectify
ingchanneleN
OSendo
thelial
nitricoxidesynthaseVNTR
variablen
umbero
ftandem
repeatsEN
PP1ectoenzymen
ucleotidep
yrop
hosphateph
osph
odieste
rase1SU
MOsmallubiqu
itin-lik
emod
ifier4UCP
2un
coup
lingp
rotein
2MTH
FR
methylenetetrahydrofolateredu
ctaseIFN120574interferon120574C
CR5C-
Cchem
okiner
eceptortype5
INSR
insulin
receptorC
SGE
conformation-sensitive
gelelectroph
oresis
ACE
angiotensin
Icon
vertingenzyme
HFE
hem
ochrom
atosisgenePTP
N1proteintyrosin
Phosph
atase1B
CADcoron
arya
rteryd
iseaseCE
TPcho
leste
ryleste
rtransferp
roteinA
T1R
angiotensin
IreceptorMMP3
matrix
metalloproteinase
3CA
Scoronary
artery
steno
sisB
ChEK
Butyrylcho
linesteraseK
DNdiabetic
neph
ropathyAT
2Rang
iotensin
IIreceptorV
EGFvascularepith
elium
grow
thfactorD
Rdiabeticretin
opathy
PDR
proliferativ
ediabetic
retin
opathy
NPD
Rno
n-PD
RDFU
diabetic
foot
ulcer
Journal of Diabetes Research 13
321 T1DM Related Genes All the studies in this subgroupincluding 12 studies [22ndash33] were in a case control studydesign using PCR (polymerase chain reaction) [33] PCR-RFLP (restriction fragment length polymorphism) [22 2325 26 32] PCR-SSP (single specific primer) [24 28ndash32]and ARMS-PCR (amplification refractory mutation systemPCR) [27] method In all studies both men and women wereincluded and the overall 2519 subjects were under 40 yearsold
Association of interleukins including IL-18 (interleukin)and IL-12 with T1DM revealed that the minus137CG polymor-phism of IL-18 had significant association with T1DM (119875 =0037 119875 = 00001) while no significant relation was observedbetween minus607AC variant of this gene and T1DM [24 28]Investigating IL-12 also showed that there was a significantassociation between +1188AC polymorphism of this geneand T1DM (119875 = 0035) [30]
In 2 studies the association of +49AG variant of CTLA-4 (cytotoxic T lymphocyte associated antigen 4) was investi-gated and it was revealed that there was a positive significantassociation between AG genotype and T1DM (119875 = 001 119875 lt0001) [22 32] One of these studies also revealed that therewas a negative relation betweenAA genotype and T1DM [32]
Vitamin D receptor (VDR) was investigated in 2 studies[25 26] Both of them assessed the association of FokI BsmIApaI and TaqI variants of VDR with T1DM In one studywhichwas performed on 114 subjects Aa (119875 = 0003) FF (119875 =0008) and Bb (119875 = 0014) genotypes were shown to be pos-itively associated with T1DM but no significant associationwas observed between TaqI polymorphism and T1DM [25]Another study which was performed on 187 subjects showedno significant association between T1DM and FokI BsmIand ApaI However TT genotype was observed to be morefrequent in controls (119875 = 0007) and negatively associatedwith T1DM [26]
Different polymorphisms of TAP2 and their associationwith T1DM were investigated in 191 subjects It was shownthat Ile379Val and Stop687Gln had significant associationwith T1DM (119875 = 0001 and 119875 = 0013 resp) Other variantsof TAP2 (transporter 2 ATP-binding cassette) includingAla565Thr Arg651Cys and Ala665Thr were not associatedwith T1DM significantly [27]
Association of alleles A2ndashA9 of CD4 with T1DM wasassessed in 200 subjects It was revealed that A3 allele hadnegative (119875 = 0025) and A5 had positive (119875 = 0001)significant association with T1DM [33]
Association of some other genes including osteopontin(rs1126772 polymorphism) integrin 1205724 (rs1449263 polymor-phism) CD44 (rs8193 polymorphism) and TGF120573 (trans-forming growth factor) (+915CG polymorphism) was alsoinvestigated in 2 studies and no significant relation wasobserved between these variants and T1DM [23 29]
322 MODY In this category only one study was found [34]and the association of Val255Met polymorphism of HNF120572and diabetes was investigated in 101 subjects includingMODY subjects their relatives and healthy controls [34]Thestudy was designed as a case control association study andPCR-RFLP and direct sequencing was used for genotyping
of variants Val255Met mutation in this investigation wasobserved in MODY subjects and their relatives but not incontrol group
323 T2DM Related Genes In this subgroup 42 studieswere assessed and all of them were designed as case controlassociation studies [22 35ndash68 70ndash75] except for one whichwas cross sectionally designed [69] In 33 studies PCR- RFLPwas used for genotyping [22 36ndash38 40ndash54 56 58ndash61 63ndash66 69 72ndash75] In 5 of them PCR was used [35 57 62 70 71]and the remaining studies PCR-SCA [39] real-timePCR [55]ARMS-PCR [66] Gap PCR [67] and CSGE (conformation-sensitive gel electrophoresis) sequencing [68] as the genotyp-ing method were applied
Association between two polymorphisms of TCF7L2including rs7903146 (CT) and rs12255372 (GT)was assessedin three studies [38 48 53] In one study investigatingrs7903146 (CT) in 466 subjects significant difference in thefrequency of CC and CT genotypes was observed betweenT2DM and control group (119875 = 0045) [38] However inanother study this polymorphism showed a positive signifi-cant associationwith TT genotype in T2DM (119875 = 0008) [53]Investigation of rs12255372 (GT) polymorphism of TCF7L2in another study showed that among 491 subjects there wasa positive significant association between TT carriers andT2DM (119875 = 0014) [48]
Investigating the association of calreticulinwith T2DM in650 subjects showed two mutations only in case group 9 bpdeletion of 397ndash399 codons and GgtT mutation at IVSII-142[39]
Association of estrogen receptor 120572 and its PvuII(PPPppp) and XbaI(XXXxxx) polymorphism with T2DM intwo studies was assessed [40 49] In one study the significantassociation of PvuII and XbaI polymorphisms with T2DMwas observed (119875 = 0014 and 119875 = 0002 resp) [40] Inanother study it was revealed that pooled Pp+pp and XX+xxmale carriers have positive significant associationwithT2DM(119875 = 0001 and 119875 = 0026 resp) [49]
Association of Pro12Ala polymorphism of PPAR120574 withT2DMwas investigated in three studies [41 69 75] Negativesignificant association of AlaAla genotype with T2DM wasobserved in two studies (119875 = 0003) [41 75] AlaPro carrierswere shown to be positively associated in one study [41] andnegatively associated in another study [75] with T2DM (119875 lt0001 and 119875 = 0003 resp) However in the third studyno significant association was observed between Pro12Alapolymorphism of PPAR120574 and T2DM [69]
Association of different polymorphisms of ApoAI withT2DM was investigated in two studies [43 72] In one studyinvestigation of MSPI polymorphism showed no significantassociation with T2DM [43] In another study it was shownthat G-75A polymorphism of ApoAI was not associated withT2DM while a significant association was found betweenC+83T polymorphism and T2DM (119875 = 0028) [72]
Two studies assessed the association of minus156GgtC poly-morphism of CXCL5 with T2DM [44 65] In one studypositive significant association of GC carriers (119875 = 0006)and negative association of GG carriers (119875 = 001) was foundbetween diabetic patients and healthy controls [44] and
14 Journal of Diabetes Research
in another study positive significant association was foundbetween GC or CC carriers and T2DM (119875 = 0009) [64]
Adiponectin and its association with T2DM were inves-tigated in two studies [56 73] In one study two variantsincluding +45TG and minus11391GA were investigated but nosignificant relation was found between these two polymor-phisms and T2DM [56] However in another study investi-gating +45TG polymorphism of adiponectin it was revealedthat nonobese T2DM subjects had significantly higher TTgenotype (119875 = 004) [73]
In one study that investigated insulin receptor gene thefollowing mutations were found only in T2DM 511CgtA514TgtG 586 and 628TgtA on exon 2 694GgtC 680GgtA onexon 3 1627AgtT on exon 8 ATgtTG on intron 9 2007CgtCTon exon 9 2595CgtCT and 2669GgtCG on exon 13 2706 and2717CgtG 2752CgtT and 2753CgtG on exon 14 and 3471TgtAand 3516TgtG on exon 19 These mutations were not seen incontrol subjects [68]
Other variants which had significant association withT2DM included haptoglobin (allele 2-2) leptin (G-2548Apolymorphism) paraoxonase 2 (Ser311Cys polymorphism)GST (glutathione-S-transferase) M1 and GSTM1GSTT1interaction calpain-10 (SNP (single nucleotide polymor-phism) 43) IRS-1 (G972R polymorphism) and IRS-2(G1057D polymorphism) VDR (vitamin D receptor) (TaqIpolymorphism) KCNJ11 (E23K polymorphism) eNOS(endothelial nitric oxide synthase) VNTR (intron 4 ab pol-ymorphism) resistin (minus420CG polymorphism) and ACE(InsertionDeletion) [35ndash37 45 47 50 55 57 58 64 70]
In contrast to above variants CTLA4 (+49AG poly-morphism) HNF-1120572 (Ala98Val polymorphism) GLP-1R(glucagon-like peptid 1 receptor) (Thr149Met polymor-ohism) SLC30A8 (Arg325Trp polymorphism) GSTP1(Ile105Val polymorphism) glucokinase (minus30GA polymor-phism) SDF-1120573 (stromal derived factor -1 120573) (G801A poly-morphism) ApoE (apolipoprotein E) ENPP1 (ectoenzymenucleotide pyrophosphate phosphodiesterase 1) (K121Q poly-morphism) SUMO4 (small ubiquitin-like modifier 4)Met55Val polymorphism) MTHFR (C677T polymorphism)UCP2 (uncoupling protein 2) (minus866GA polymorphism)5HTTLPR IL-4 (minus590CT polymorphism) IFN-120574 (inter-feron 120574) (+874TA polymorphism) CCR5 (C-C chemokinereceptor type 5) (12057532mutation) HFE (hemochromatosisgene) (H63D C282Y PTPN1 (protein tyrosin Phosphatase1B)minus51delA minus451AgtG minus467TgtC minus1023CgtA minus1045GgtAminus1286 3 bp del ACA minus1291 9 bp del CTAGACTAA poly-morphisms) were not significantly associated with T2DM[22 42 46 50ndash52 54 59ndash63 66 67 71 74]
324 Genes Related to Insulin Resistance In this subgroupfour studies were assessed and all were designed as case-control association studies Three studies used PCR-RFL [7678 79] and one study used real-time PCR [77] for genotyping
The studies assessed in this subgroup showed a positiveassociation of TG carriers of +45TG polymorphism ofadiponectin (119875 = 0032) and Ala allele carriers of Pro12Alapolymorphism of PPAR120574 (119875 = 0036) with T2DM [76 77]A positive significant association of ff carriers of VDR wasalso shown (FokI polymorphism) (119875 = 002) and negative
association of 148insG carriers of PTPN1 (148insG polymor-phism) (119875 = 0041) with insulin resistance index [7879] However no significant association was shown betweenadiponectin receptor-2+795GA and T2DM [76]
325 Genes Related to Cardiovascular Disease in DiabetesDesign of all 11 studies in this subgroup was case-controlassociation study [80ndash84 86ndash90] except one study which wasdesigned as cross sectional [85] PCR-RFLP was used in all ofthem for genotyping [80ndash88 90] except in one study whichused ARMS-PCR method [89]
Paraoxonase 1 (163TA polymorphism) was the only vari-ant in this subgroup which was not significantly associatedwith atherosclerosis risk in T2DM [80] Investigation ofanother polymorphism of Paraoxonase 1 (Q192R) revealedthat diabetics with CAD had significant increase in RRgenotype (119875 lt 005) [81]
Investigating B1 and B2 alleles of CETP TaqI B allele in400 subjects showed that pooling of B1B1+B1B2 and B1B1genotypes had significant association with T2DM and CAD(119875 lt 001) On the other hand assessing the G894T poly-morphism of eNOS showed positive significant associationbetween TG and TT carriers and CAD (119875 lt 005) It was alsoshown that concomitant presence of NOS3 T allele and CEPTB1 allele was significantly associated with T2DM (119875 = 0004)and CAD (119875 = 0002) [83]
Investigation of apolipoprotein E (E2 E3 and E4) allelesshowed the association of E2 and E4 alleles with CAD(119875 lt 0001) [84 87] Also it was shown that interactionof butyrylcholinesterase (BChE K) and apolipoprotein E(ApoE) was associated significantly with CAD and diabetesApoE4BChE K had significant association with lipid profilesas well (119875 lt 005) [87]
Adiponectin +276GT and +45TG were significantlyassociated with CAD (119875 = 0023 and 0033 resp) [82] whileinvestigating minus1612 5A6A polymorphism of MMP-3 (matrixmetalloproteinase 3) showed a significant association withCAS (coronary artery stenosis) (119875 = 0008) [86]
In addition A1166C polymorphism of AT1R (angiotensinI receptor) and minus420CG polymorphism of resistin in dia-betic patients with CAD revealed significant association withdiabetes 119875 = 001 and 119875 = 0009 respectively [84 85]
Another study showed insertion(I)deletion(D) polymor-phismof angiotensin converting enzyme (ACE)DDgenotypewas significantly associated with higher blood pressure (119875 =0026) [89]
Factor V Leiden (G1691A polymorphism) prothrombin(G20210A polymorphism) and MTHFR (methylenetetrahy-drofolate reductase) (C677T polymorphism) were the vari-ants which were not significantly associated with CAD andT2DM in this subgroup [88]
326 Genes Related to Diabetic Nephropathy All of 15 studiesin this subgroup were designed as case-control associationstudies [91ndash106] In 7 studies PCR-RFLP was used forgenotyping [92ndash95 99 102 103] in four studies PCRwas used[98 101 104 105] and in 4 of them both PCR and PCR-RFLPwere used [91 96 97 100]
Journal of Diabetes Research 15
Studying the association of 163AG polymorphism ofSUMO4 showed a positive significant association betweenAA carriers and diabetic nephropathy (119875 lt 005) [93]
Studying the interaction of eNOS4ab and G894Trevealed positive significant association between 4a or 894Tallele carriers and macro- and microalbuminuria (119875 = 001119875 = 002 resp) [91] It was observed that the interaction ofeNOS (G894T polymorphism) andACE (ID alleles) was sig-nificantly associated with more frequent macroalbuminuria(119875 = 0035) [97]
It has also been shown that interaction of eNOS (G894Tpolymorphisms) and MTHFR (C677T and A1298C poly-morphisms) eNOS T1298 C and eNOS T677 T carriershad positive significant association with macroalbuminuriaIn addition significant association of eNOS GT+TT carrierswith lipid profile (119875 lt 005) was shown in this study [99]
C677T andA1298C polymorphisms ofMTHFRwere alsoinvestigated in another study revealing that 677T 1298Cand 677T1298C carriers were significantly associated withmacroalbuminuria (119875 lt 0001) Positive significant asso-ciation when pooling CT+TT genotypes and 677T1298Cwas also found with microalbuminuria (119875 lt 0001) [103]Investigating the interaction of MTHFR (A1298C C677Tpolymorphisms) and ACE (ID alleles) showed a positivesignificant association of ACE D677T (119875 = 0035) and ACED1298C (119875 = 0012) genotypeswithmacroalbuminuria [96]
ACE (ID alleles) polymorphisms were investigated inthree studies In one study positive significant association(119875 lt 001) between DD carriers and progression but notdevelopment of albuminuria was observed [104] In anotherstudy in nephropathic subjects association of DD carriersand T2DM (119875 = 0006) but not nephropathy was revealed[105] However another study did not show significant asso-ciation of ACE with macroalbuminuria [98] Interaction ofACE (ID alleles) with Factor V Leiden (G1691A polymor-phism) was not significant [100]
Association of interleukins including IL-4 and IL-10 withdiabetic nephropathy was also investigated in two studiesStudy of minus592CA polymorphism of IL-10 revealed positivesignificant association between CC carriers and nephropathy(119875 = 0001) [94] and study ofminus590CTpolymorphismof IL-4revealed positive significant association between CT carriersand nephropathy (119875 lt 0001) [101]
Other significant associations between variants and dia-betic nephropathy included AT2R (angiotensin II recep-tor) (minus1332GA polymorphism) VEGF (vascular epitheliumgrowth factor) (+405GC polymorphism) and VDR (TaqIpolymorphism) [92 95 102] ApaI polymorphism of VDRwas not significantly associated with diabetic nephropathy[102]
327 Genes Related to Diabetic Retinopathy All of the 3studies in this subgroup were conducted as case-controlassociation studies [106ndash108]
Investigating nullpositive genotype of GSTM1 in a studywhich used ARMS-PCR for genotyping revealed that nullgenotype is significantly associated with diabetic retinopathy(119875 lt 005) [106] This result was confirmed in another study
by using multiplex PCR as genotyping [107] although nosignificant association between GSTT1 and retinopathy wasfound in this study [107]
Investigating +405GC polymorphism of VEGF alsorevealed positive significant association between GG carriersand diabetic retinopathy (119875 = 0005) [108]
328 Genes Related to Diabetic Foot Ulcer In this subgrouponly one study was found [109] which was case-controldesigned and used ARMS-PCR for genotyping In this studyassociation of minus7CT and minus2578CA polymorphisms ofVEGF with diabetic foot ulcer (DFU) was investigated and apositive significant association betweenAA carriers andDFU(119875 = 003) was observed But no significant association wasfound between minus7CT of VEGF and DFU [109]
4 Discussion
Diabetes mellitus is the eighth most frequent disease leadingcause of death throughout the world and now ranks the fifthfollowing communicable diseases cardiovascular diseasecancer and injuries [110] Prevalence of diabetes mellitus isincreasing worldwide [6]
Type 2 diabetes is the most frequent type of diabetesmellitus [110 111] Multiple genes and environmental factorsaffect the prevalence of T2DM Systematic review and meta-analysis studies have assessed the association between dif-ferent genes and T2DM Glutathione-S-transferase includingGSTMI GSTM1 and GSTP1 are important genes and theirassociation with diabetes has been investigated in two meta-analysis studies [112 113] It was revealed that null genotypeof both GSTM1 and GSTT1 could be as a risk factor fordiabetes while no significant association was found betweenGSTP1 and diabetes [112 113] These results are in linewith our finding and confirming the association of the nullgenotype of GSTT1 and GSTM1 with T2DM in Iranianpopulation [50] The relation between GSTT1 and GSTM1and diabetic retinopathy has also been shown in Iranianpopulation [106 107]
MTHFR is another important gene in association withT2DM and other related complications No associationof C677T polymorphism of MTHFR gene was found inAfricans Asians and Caucasians [114] MTHFR is a genewhich is involved in DNA methylation and synthesis andregulated folate activity It has been reported that mutanthomozygote and heterozygote of C677T polymorphism ofMTHFR increase plasma homocysteine which is an impor-tant factor leading to diabetic nephropathy (DN) and as aresult C677T polymorphism of MTHFR can be associatedwith the development of DN In Caucasians this associationhas also been observed [115] In Iranian population in linewith other populations no significant association was foundbetween MTHFR polymorphisms and T2DM [63] althoughsignificant association of 677T and 1298C alleles with diabeticnephropathy was observed [87] Interaction of two polymor-phisms and also interaction of MTHFR polymorphisms withother genes such as ACE and eNOS showed an associationwith development of DN [96 99]
16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
2 Journal of Diabetes Research
highest amongst developing countries Previous reports ontotal urban population of Middle Eastern countries show theprevalence of T2DM as 34 in Sudan 20 in United ArabEmirates 85 in Bahrain and 121 in India [7]
DiabetesMellitus is categorized into the following groupsType 1 diabetes mellitus (T1DM) includes 5ndash10 of dia-
betic patients Cellular-mediated autoimmune destruction ofthe beta-cells of the pancreas results in T1DM It classicallyoccurs in juveniles and affected patients are dependent oninsulin injection in their lifetime and are very prone to ketosis[1 8 9]
T2DM includes 90ndash95 of patients with diabetesPatients with type 2 diabetes may be asymptomatic for longperiod of time Vascular complications such as nephropathyneuropathy retinopathy and cardiovascular disease maydevelop in these patients The impact of genetic componentappears to be stronger in T2DM compared to T1DM [1 8 9]
Gestational diabetes mellitus (GDM) is another typewhich is observed during pregnancy and the prevalence mayrange from 1 to 14 in all pregnancies [1 8 9]
MODY (maturity onset diabetes of young) is monogenicform of diabetes comprised of several types with variousfeatures which is consisting of 1ndash5 of patients diagnosed asT2DMTheonset of this type of diabetes is normally before 25years and its treatment is independent of insulin MODY inits different forms is inherited in autosomal dominant patternand presents as a result of mutation in transcription factorsgenes including HNF4120572 (hepatocyte nuclear factor) HNF1120573IPF1 (insulin promoter factor) and neuro-D1 [1 8 9]
There are also other types of diabetes which are con-sidered as secondary to other conditions for example anydamage to pancreas such as removal of pancreatic tissuetrauma pancreatic carcinoma and infection or underlyingdiseases including endocrine diseases that alter different hor-mones secretion which are antagonist to insulin resulting invarious clinical manifestations such as acromegaly Cushingrsquossyndrome pheochromocytoma glucagonoma somatostati-noma and diabetes Diabetes (or carbohydrate intolerance)is also found in increased frequency with a large numberof genetic syndromes such as Wolfram syndrome whichcauses diabetes mellitus diabetes insipidus and other neu-rodegenerative disorders MELAS (mitochondrial myopathyencephalopathy lactic acidosis and stroke) which is pre-sented with myopathy and encephalopathy caused by mito-chondrial mutation MIDD (maternally inherited diabetesand deafness) which causes diabetes and IPEX (immune dys-regulation polyendocrinopathy enteropathy and X-linkedsyndrome) which is X-linked and alters immune system andcauses multiple endocrine problems [1 8 9]
Diabetes mellitus is a multifactorial disease with bothenvironmental and genetic causes affecting its presence andincidence Genome wide association studies revealed thegenetic heterogeneity of diabetes and the fact that differencein ethnicity can result in different susceptible genes associatedwith diabetes [10 11] Studies on candidate genes related todiabetes revealed that several genes including PPRAG (per-oxisome proliferator-activates receptor gamma) IRS1 and2 (insulin receptor substrate) KCNJ11 (potassium inwardlyrectifying channel) and HNFA are associated with T2DM
Genome wide association studies (GWAS) showed that manygenes including Calpain 10 and TCF7L2 (transcription factor7-like 2) are associated with T2DM HHEX (hematopoiet-ically expressed homeobox) SLC30A8 (solute carrier fam-ily 30 (zinc transporter) member 8) CDK2AB (cyclin-dependent kinase inhibitor 2AB) and IG2BP2 (insulin-likegrowth factor 2) are other genes which have been shown to beassociated with T2DM based on GWAS Some of these genesare expressed in beta cells or involved in insulin secretionpathways [12 13] Other candidate genes in associationwith T2DM include PPAR120574 ACE (angiotensin convertingenzyme) MTHFR (methylene tetrahydrofolate reductase)FABP2 (fatty acid binding protein-2) and FTO (fat massand obesity associated gene) [14] GWAS was carried out inmany populations including Finnish French and AmericanCaucasians and showed different loci on most of the chro-mosomes associated with T2DM [15] Systematic review andmeta-analysis studies also confirmed the association of somegenes such as PGC-1120572 (peroxisome proliferator-activatedreceptor gamma coactivator-1120572) and adiponectin with T2DM[16 17] The genetic loci associated with T1DM have alsobeen examined For example insulin (INS) gene VNTRs(variable number of tandem repeats) with a protective effectis a variants related to T1DM In addition PTPN22 (proteintyrosin phosphatase) CTLA4 and IL2RA genes have alsobeen shown as candidates for T1DM due to their role in T-cell signaling Studies have also confirmed the associationbetween IFIH1 CYP27B1 and CLEC16 which are importantin immune system and T1DM [18]
There is no inclusive information for genetic associationstudies of diabetes in Middle Eastern population includingIranian population In order to make a comprehensiveapproach we aimed to collectively investigate and gather datafor association between genetic variants and type 2 diabetesin Iranian population in a systematic review study
2 Research Design and Methods
This study is reported according to PRISMA (preferredreporting items for systematic reviews and meta-analyses)guideline [19]
21 Data Sources and Searches We systematically searchedinternational web databases Google Scholar PubMed Sco-pus and Persian web databases IranMedex and Magiran toinvestigate the association of genetic variants with diabetesand its complications in Iranian population up to January2014 The search terms were ldquogenerdquo ldquopolymorphismrdquo ldquodia-betesrdquo ldquodiabetesrsquo complicationsrdquo nephropathy retinopathyneuropathy foot ulcer and CAD (coronary artery disease)and their MeSH terms and Persian equivalents with diabetesAt least three emails were sent to the corresponding authorof articles which were not accessible as full text or hadinsufficient data Duplicate articles and multiple publicationsfrom the same population were excluded and the mostrelevant data were used for the investigation The referencesof all selected articles were investigated
22 Study Selection We included all observational popula-tion-based studies ge100 sample size which were conducted
Journal of Diabetes Research 3
Iden
tifica
tion
Records identified through
Scre
enin
gEl
igib
ility
Inclu
ded
Eligible full texts records
Included records to systematic
database searching (n = 3029)
Records excluded by title (n = 2734)
- Excluded due to duplicatepublication (n = 106)
(n = 104)
review (n = 88)
Records excluded by full text (n = 16)
- Excluded due to data from the samepopulation (n = 13)
- Excluded due to not measuredrelevant outcomes (n = 3)
- Google scholar (n = 2000)
- PubMed (n = 300)
- Scopus (n = 557)
- Persian web databases (n = 172)
- Excluded by abstract (n = 85)
Figure 1 Flow diagram of study selection process
as case-control cohort or cross sectional According toWHO criteria diabetes mellitus was defined as FBS ge7mmolL (126mgdL) or 2 h plasma glucose ge111mmolL(200mgdL) [20] In addition we excluded animal studiesclinical trials short communications letters to editor disser-tations in vitro studies review articles and population-basedstudies conducted in pregnant women Two researchers SEand MKH independently reviewed title abstract and fulltext of each article to assess the eligible articles according toinclusion and exclusion criteria Inclusion and exclusion ofarticles were supervised by a third reviewer (OTM) in case ofconflicts There was no limitation for language
23 Data Extraction and Quality Assessment The follow-ing data were extracted and presented in an excel sheetauthor(s) year genes and SNPs patientsrsquo characteristics(sample size age and sex) city study design genotypingmethod and significant association Six selected items fromthe STROBE (strengthening the reporting of observationalstudies in epidemiology) checklist [21] was used for qualityassessment of the included studies and assessed separatelyfor each included article The below items were considered(a) clearly define the outcome and association between genevariants and diabetes (b) give the eligibility criteria (c)present key elements of study design (d) report numbers orsignificancenonsignificance statistically of outcome events(e) give characteristics of study participants and (f) describethe locations and relevant dates All studies with quality scorege3 were considered as high quality study and included in oursystematic review
24 Data Synthesis and Analysis Due to heterogeneity ingenotyping techniques and also differences in genetic variantsstudied in assessed included articles performing a meta-analysis was impossible
3 Results
31 Search Results A summary of the literature reviewprocess performed in this study is presented in a flow chartin Figure 1 In final step 88 eligible studies were includedin this study and assessed due to the inclusionexclusioncriteria [22ndash109] Table 1 shows the summary of each includedinvestigation
32 Studies Characteristics Overall 27396 diabetics andhealthy subjects were studied in this systematic review Allof the subjects were recruited from total urban populationT2DMwas themost investigated type of diabetes (42 studies)[22ndash75] Among diabetes complications diabetic nephropa-thy and CAD were the most examined respectively [80ndash105] Twelve studies were carried out on T1DM [22ndash33]The least investigated complication was diabetic foot ulcerwhich was assessed only in one study [109] Retinopathyand insulin resistance were also among the least investigatedcomplications including 3 and 4 studies respectively [76ndash79 106ndash108] Only one study assessed MODY in our review[34] All of the studies were performed on both gendersexcept for one which was performed on males [45]
Details of the included studies are described as below
4 Journal of Diabetes Research
Table1Ch
aracteris
ticso
fincludedarticlesinsyste
maticreview
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
T1DM
andcomplications
Ahm
adietal2013
[22]
CTLA
-4+49AG
60T1DM56T2
DMand
107
healthymale(M)female(F)
Kurdistan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAG
carriersandT1DM
(P=001)
Karamizadeh
etal2013
[23]
(i)Oste
opon
tinrs11
26772
(ii)Integrin1205724rs1449263
CD44
rs8193
87T1DM
and86
healthy
lt20
yrM
FSh
iraz
Case
control
PCR-RF
LPNon
significance
Rahb
ani-N
abar
etal2013
[24]
IL-18minus137C
G104T1DM
and92
healthy
9ndash32
yrM
FTabriz
Case
control
SS-PCR
Positives
ignificantassociatio
nbetweenGGcarriersandT1DM
(P=0037)
Bonakd
aran
etal2012
[25]
(i)VDRFokI
(FFFfff
)(ii)B
smI(BB
Bbbb)
ApaI
(AA
Aaaa)
(iii)TaqI
(TTTttt)
69T1DM
and45
healthy
lt35
yrM
FMashh
adCa
secontrol
PCR-RF
LP
Positives
ignificantassociatio
nbetweenAa(
P=0003)FF
(P=0008)and
Bb(P
=0014)
carrierswith
T1DMsignificant
associationbetweenffgeno
type
andhisto
ryof
ketoacidosis
(P=004)
Moh
ammadnejadetal2012
[26]
(i)VDRTaqI
(TTTttt)
(ii)V
DR
FokIB
smIAp
aI87
T1DM
and100healthy
17ndash38y
rMF
Mashh
adCa
secontrol
PCR-RF
LP
(i)Negatives
ignificant
associationbetweenTT
carriers
andT1DM
(P=0007)
(ii)N
onsig
nificance
association
betweenotherc
arrie
rsof
VDR
andT1DM
Afsharietal2011[27]
(i)TA
P2Ile379Va
l(ii)T
AP2
Stop687Gln
(iii)TA
P2Ala565Th
rArg651Cy
sAla665Th
r
87T1DM
and104healthy
lt30
yrM
FMashh
adCa
secontrol
ARM
S-PC
R
(i)Sign
ificant
association
betweenIle
379V
alandT1DM
(P=0001)
(ii)S
ignificantassociatio
nbetweenStop
687G
lnandT1DM
(P=0013)
(iii)Non
significantassociatio
nbetweenotherc
arrie
rsof
TAP2
andT1DM
Massoud
etal2009
[28]
(i)IL-18minus137C
G(ii)IL-18minus607A
C75
T1DM
and88
healthy
lt30
yrM
FTehran
Case
control
PCR-SSP
(i)Po
sitives
ignificantassociatio
nbetweenGGcarriersandT1DM
(P=000
01)
(ii)S
ignificantassociatio
nbetweenCC
geno
type
with
T1DM
(P=000
01)
(iii)Non
significance
association
betweenotherc
arrie
rsof
IL-18
andT1DM
Journal of Diabetes Research 5
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Masou
detal2007
[29]
TGF120573
+915C
G75
T1DM
and88
healthy
lt30
yrM
FTehran
Case
control
PCR-SSP
Non
significance
Masou
detal2007
[30]
IL-12+1188A
C75
T1DM
and88
healthy
lt30
yrM
FTehran
Case
control
PCR-SSP
Sign
ificant
associationbetween
AAandAC
geno
type
andT1DM
(P=0035)
Mojtahedi
etal2006
[31]
IL-18minus607A
C
minus137C
G112T1DM
and194no
n-DM
lt15
andgt15yrM
FSh
iraz
Case
control
PCR-SSP
minus137C
Candminus607A
Aminus137C
Csig
nificantassociatio
nwith
T1DM
inon
setgt
15yr
(P=0027)
Mojtahedi
etal2005
[32]
CTLA
-4+49AG
109T1DM
and331h
ealth
y0ndash
37yrM
FSh
iraz
Case
control
PCR-SSP
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenAG
carriersandT1DM
(P=000)
(ii)N
egatives
ignificant
associationbetweenAAcarriers
andT1DM
(P=000)
Zamanietal2005
[33]
CD4A2
ndashA9
92T1DM
and108healthy
gt35
yrM
FTehran
Case
control
PCR
Negatives
ignificantassociatio
nbetweenA3alleleandT1DM
(P=0025)
Positives
ignificantassociatio
nbetweenA5alleleandT1DM
(P=0001)
MODY
Tagh
avietal2009
[34]
HNF120572
Val255M
et30
MODY21
relativ
esand
50healthy25ndash35y
rMF
Mashh
adCa
secontrol
PCR-FL
Psequ
encing
Them
utationwas
foun
din
patie
ntsa
ndrelatives
butn
otin
controls
T2DM
andcomplications
Ahm
adietal2013
[22]
CTLA
-4+49AG
Said
above
Said
above
Said
above
Said
above
Non
significance
Amiri
etal2013
[35]
Haptoglob
in1-
12-12-2
134T2
DM
with
MVC
s71
T2DM
with
outM
VCs
46ndash72y
rMF
Sari
Case
control
PCR
Hp2-2
high
lysig
nificantfor
T2DM
(P=005)
And
alib
etal2013
[36]
Paraoxon
ase2
Ser311Cys
100T2
DM
and100healthy
51yrM
FIsfahan
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
CysCy
sand
CysSerc
arrie
rsand
negativ
esignificantassociatio
nof
SerSerc
arrie
rswith
T2DM
(Plt005)
Kohanetal2013
[37]
LeptinG
-2548A
100T2
DM
and100healthy
44ndash6
6yrMF
Arsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersandT2
DM
(P=000
4)
Alamietal2013
[38]
TCF7L2
rs7903146
(CT)
233T
2DM
and233controls
gt40
yrM
FGorgan
Case
control
PCR-RF
LPCC
andCT
geno
typessignificant
differenceb
etweenT2
DM
and
controls(P
=0045)
Mahmazietal2013
[39]
Calre
ticulin
120T2
DM
and530controls
43ndash6
6yrMF
Zanjan
Case
control
PCR-SC
A9b
pdeletio
nof
397ndash399codo
nsGgtTmutationatIV
SII-142in
T2DM
notincontrols
6 Journal of Diabetes ResearchTa
ble1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Moh
ammadietal2013
[40]
(i)ER120572PvuII(PPPp
pp)
(ii)E
R120572XbaI(XX
Xxxx)
174T2
DM
and174ND
35ndash6
5yrMF
Jahrom
Case
control
PCR-RF
LP
(i)Sign
ificant
associationwith
T2DM
(P=0014)
TC(P
=0007)and
TG(119875=0005)fem
alec
arrie
rs(ii)S
ignificantassociatio
nwith
T2DM
(119875=0002)TC
(119875=0003)andTG
(119875=0009)
femalec
arrie
rs
Motavallianetal2013
[41]
PPAR-1205742Pro12A
la100T2
DM
and100healthy
51yrM
FIsfahan
Case
control
PCR-RF
LP
Negatives
ignificantassociatio
nbetweenAlaA
lacarriers
(119875lt0001)a
ndpo
sitive
significantassociatio
nbetween
AlaPro
carrierswith
T2DM
(119875lt0001)
Sepahi
etal2013
[42]
HNF-1120572Ala98Va
lGLP
-1RTh
r149Met
100T2
DM
and50
healthy
controlsle35
andgt35
yrM
FMashh
adCa
secontrol
PCR-RF
LPNon
significance
Sheikh
haetal2013
[43]
APO
A1M
SP-I
200T2
DM
and200healthy
418yrM
FYazd
Case
control
PCR-RF
LPNon
significance
Yagh
oubietal2013
[44]
CXCL
5minus156GgtC
100T2
DM54y
rand
100healthy
56yrM
FArdabil
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GCcarriers(119875=0006)a
ndnegativ
esignificantassociatio
nof
GGcarrierswith
T2DM
(P=001)
Bahreini
etal2012
[45]
Calpain-10SNP4
3(AG)
102T2
DM
and100healthy
40ndash70y
rM
EastAzerbayjan
Case
control
PCR-RF
LPGallelea
srisk
factor
ofT2
DM
(P=0037)
Derakhshanetal2012
[46]
SDF-1120573G
801A
200T2
DM
and200healthy
40yrM
FRa
fsanjan
Case
control
PCR-RF
LPNon
significance
Haghani
etal2012
[47]
(i)IRS-1G
972R
(ii)IRS
-2G
1057D
336T2
DM
and341h
ealth
y44
ndash63y
rMF
Ilam
andKe
rmanshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
GR(P
=0001)andRR
(119875=00001)carrie
rswith
T2DM
(ii)P
ositive
significant
associationbetweenGDcarriers
andT2
DM
(P=0016)
Alamietal2012
[48]
TCF7L2
rs12
255372
(GT)
236T2
DM
and255healthy
gt37
yrM
FGorgan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersandT2
DM
(P=0014)
Meshk
anietal2012
[49]
(i)ER120572PvuII(PPPp
pp)
(ii)E
R120572XbaI(XX
Xxxx)
155T2
DM
and377controls
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
pooled
Pp+pp
malec
arrie
rs(P
=0001)with
T2DM
(ii)P
ositive
significant
associationof
pooled
XX+
xxmalec
arrie
rs(P
=0026)
with
T2DM
Journal of Diabetes Research 7
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Moasser
etal2012
[50]
GST
M1p
resentnull
GST
T1presentnull
GST
P1Ile105Va
l
171T
2DM
and169healthy
25ndash6
5yrMF
Shira
zCa
secontrol
PCR-RF
LP
GST
M1-n
ull(P=0016)
and
interactionof
GST
M-nullG
STT1-null
(119875=0022)significant
associationwith
T2DM
Moh
addese
tal2012
[51]
SLC3
0A8Arg325Trp
125T2
DM
and125controls
40ndash70y
rMF
Azarbayjan
Case
control
PCR-RF
LPNon
significance
Oladi
etal2012
[52]
Glucokinaseminus30GA
542subjects
18ndash6
5yrMF
Mashh
adCr
osssectio
nal
PCR-RF
LPNon
significance
Palizbanetal2012
[53]
TCF7L2
rs7903146
(CT)
110T2
DM
and80
healthy
46ndash6
7yrMF
Isfahan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersandT2
DM
(P=0008)
Tabatabaei-M
alazyetal2012
[54]
ApoE
E3-E3
E2-E3
E4-E3
156T2
DM
and155healthy
25ndash6
5MF
Tehran
Case
control
PCR-RF
LPNon
significance
Ghasemietal2012
[55]
KCNJ11
E23K
358T2
DM
and388healthy
41ndash6
9yrMF
Rasht
Case
control
Realtim
ePCR
Positives
ignificantassociatio
nbetweenKK
carriersandob
ese
T2DM
(P=0037)
Ranjbare
tal2011[56]
Adipon
ectin
+45TG
minus113
91GA
244T2
DM
and99
healthy
37ndash6
5yrMF
Rafsanjan
Case
control
PCR-RF
LPNon
significant
Mehrab-Moh
seni
etal2011[57]
eNOSVNTR
intro
n4ab
220T2
DM
and96
healthy
53plusmn15yrM
FRa
fsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenaa
orab
carriersand
T2DM
(P=002)
Nosratabadi
etal2011[58]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DM
and100healthy
40yrM
FRa
fsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandT2
DM
(Plt0001)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandT2
DM
Saberietal2011[59]
ENPP
1K121Q
155T2
DM
and377healthy
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LPNon
significance
Fallahetal2010
[60]
SUMO4Met55Va
l(16
3AG
)50
T2DM
and50
healthy
25ndash4
5yrMF
Tehran
Case
control
PCR-RF
LPNon
significance
Heidarietal2010
[61]
UCP
2minus866G
A75
T2DM75NDob
esea
nd75
NDno
nobese35ndash76
yrM
FTehran
Case
control
PCR-RF
LPNon
significance
Nazem
etal2010
[62]
5HTT
LPRSSSLLL
90T2
DM
and90
healthy
54ndash6
6yrMF
Shira
zCa
secontrol
PCR
Non
significance
Bazzaz
etal2010
[63]
MTH
FRC677T
401T
2DM74NDob
esea
nd207
NDno
nobese30ndash
63yrM
FTehran
Case
control
PCR-RF
LPNon
significance
Emam
gholipou
retal2009
[64]
resistin
minus420C
G47
T2DM
and66
healthy
58plusmn9y
rMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandT2
DM
(P=000
9)
Hasani-R
anjbar
etal2009
[65]
CXCL
5minus156G
C230T2
DM
and120healthy
40ndash6
3yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGCor
CCcarriersand
T2DM
(P=000
4)
8 Journal of Diabetes ResearchTa
ble1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
KazemiA
rababadi
etal2009
[66]
IL-4minus590C
TIFN-120574+874T
A160T2
DM
and160healthy
38plusmn9y
rMF
Rafsanjan
Case
control
PCR-RF
LPARM
S-PC
RNon
significance
Arababadi
etal2009
[67]
CCR5
12057532mutation
200T2
DM
and300healthy
40plusmn9y
rMF
Rafsanjan
Case
control
Gap-PCR
Non
significance
Kazemietal2009
[68]
INSR
128T2
DMgt
40yrM
FTehran
Case
control
PCR
CSGE
sequ
encing
Follo
wingmutations
werefou
ndon
lyin
T2DM
511CgtA514Tgt
G586and
628TgtAon
exon
2694GgtCand680GgtAon
exon
31627AgtTon
exon
8ATgtTG
onintro
n9
2007Cgt
CTon
exon
92595Cgt
CTand2669GgtCGon
exon
132706
and2717Cgt
G2752CgtT
2753Cgt
Gonexon
143471Tgt
Aand3516Tgt
Gon
exon
19
Mirz
aeietal2009
[69]
PPAR120574
2Pro12A
la78
norm
al78ob
ese78
T2DM
and78
obeseT
2DM25ndash64
yr
MF
Tehran
Crosssectio
nal
PCR-RF
LPNon
significance
Nikzamiretal2008
[70]
ACEinsertion(I)
deletion(D
)170T2
DM
and144healthyMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(P=002)
Sharifi
etal2008
[71]
HFE
H63D
C282Y
101T
2DM
and101h
ealth
y55plusmn11yrM
FZa
njan
Case
control
PCR
Non
significance
Besharatietal2007
[72]
(i)Ap
oA-IG
-75A
(ii)A
poA-
IC+8
3T215subjects26ndash
64yrM
FTehran
Crosssectio
nal
PCR-RF
LP
(i)Non
significantassociatio
nbetweenG-75A
carriersand
T2DM
(ii)P
ositive
significant
associationbetweenCT
carriers
andT2
DM
(P=0028)
Hasani-R
anjbar
etal2007
[73]
Adipon
ectin
+45TG
80T2
DM
obese72
T2DM
nono
beseand
70healthy
25ndash6
4yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersand
nono
bese
T2DM
(P=004)
Meshk
anietal2007
[74]
PTPN
1minus51delA
minus451AgtGminus467TgtC
minus1023Cgt
Aminus1045GgtAminus1286
3bpdel
ACAminus1291
9bpdel
CTAG
ACTA
A
174T2
DM
and412healthy
23ndash79MF
Tehran
Case
control
PCR
sequ
encing
PCR-RF
LPNon
significance
Meshk
anietal2007
[75]
PPAR120574
Pro12Ala
412T2
DM
and284healthy
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LPNegatives
ignificantassociatio
nbetweenProAlaor
AlaA
lacarriersandT2
DM
(P=0003)
Journal of Diabetes Research 9
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
T2DM
patie
ntsa
ndinsulin
resistance
Nam
varanetal2012
[76]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin
receptor-2+795G
A
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTG
carriersandT2
DM
(P=0032)
(ii)N
onsig
nificantassociatio
nbetween+7
94GA
carriersand
insulin
resistance
Nam
varanetal2011[77]
PPAR120574
Pro12Ala
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
Realtim
ePCR
Positives
ignificantassociatio
nbetweenAlaallelecarriersand
T2DM
(P=0036)
Hossein-nezhadetal2009
[78]
VDRFokI
(FFFfff
)105T2
DM55plusmn10yrM
FTehran
Case
serie
sPC
R-RF
LPPo
sitives
ignificantassociatio
nbetweenffcarriersandinsulin
resistanceind
ex(P
=002)
Moo
sapo
oretal2007
[79]
PTPN
1148insG
71T2
DM
and264ND
20ndash80y
rMF
Tehran
Case
control
PCR-RF
LP
Negatives
ignificantassociatio
nbetween148insGcarriersand
insulin
resistanceind
ex(119875=0041)
T2DM
patie
ntsa
ndheartd
iseases
Bayatm
akoo
etal2013
[80]
Paraoxon
ase116
3TA
(L55M)
105CA
DD
Mand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPNon
significance
Bayatm
akoo
etal2012
[81]
Paraoxon
ase1575Ggt
A(Q
192R
)105DMCADand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenRR
carriersand
CADD
M(Plt005)
Estegh
amatietal2012
[82]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin+276G
T114
CADD
Mand127DM
42ndash71yrMF
Tehran
Case
control
PCR-RF
LP
(i)Negatives
ignificant
associationbetween45TT
carriersandCA
D(P
=0033)
(ii)P
ositive
significant
associationbetween276G
GcarriersandCA
D(P
=0023)
Rahimietal2012
[83]
eNOSG8
94T
CETP
B1
102CA
DD
M105
CADN
D101
DMand
92ND45ndash66
yrM
FKe
rmanshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
concom
itant
presence
ofNOS3
TalleleandCE
PTB1
allelewith
T2DM
(P=000
4)andCA
D(119875=0002)
Assalietal2011[84]
AT1RA116
6C145CA
DD
Mand164CA
D
lt50
andge50
yrM
FMashh
adCa
secontrol
PCR-RF
LPPo
sitives
ignificantassociatio
nof
ACandCC
carrierswith
DM
(119875=001)
Emam
gholipou
retal2009
[85]
Resistin
minus420C
G113CA
Dwith
andwith
outD
M
58plusmn9yrM
FTehran
Crosssectio
nal
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDM
(119875=0009)
10 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Fallahetal2010
[86]
MMP-3minus1612
5A6A
305CA
DD
Mand313DM
61plusmn9yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetween6A
6AcarriersandCA
S(P
=0008)
Vaisi-Raygani
etal2010
[87]
BChE
KG1
615A
APO
EE2
E3E4
118DM162
CADN
D172
DMCADand
179healthy
42ndash6
8yrMF
Kerm
anshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GAA
Aand
E4carrierswith
CADandDM
(Plt005)
Positives
ignificantassociatio
nof
BChE
KAp
oE4carrierswith
CADand
DM
(Plt005)
Sign
ificant
associationof
BChE
KAp
oE4with
lipid
profi
le(119875lt005)
Rahimietal2009
[88]
Factor
VLeidenG
1691A
Prothrom
binG2
0210A
MTH
FRC677T
65CA
DD
M52CA
DN
Dand
59healthy46
064y
rMF
Kerm
anshah
Case
control
PCR-RF
LPNon
significance
Nakhjavanietal2007
[89]
ACEID
82DM
with
hypertensio
nand87
DM
with
outh
ypertension
49ndash6
3yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
hypertensio
n(P
=0026)
Vaisi-Raygani
etal2007
[90]
Apolipop
roteinE2E3
E4
152CA
DD
M262
CADN
D
and300healthy35ndash73y
rMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nof
E2andE4
allelec
arrie
rswith
CAD(Plt0001)
T2DM
patie
ntsa
ndneph
ropathy
Rahimietal2013
[91]
eNOS4abG
894T
63T2
DMm
icroalbu
minuria
57T2
DMm
acroalbu
minuria
52T2
DMnormoalbum
inuria
121D
Nand
101h
ealth
y45ndash6
6yrMF
Kerm
anshah
Case
control
PCR
PCR-RF
LP
Positives
ignificantassociatio
nof
4aor
894T
allelecarriersand
macro-(P=001)o
rmicroalbu
minuria(P
=002)
Rahimietal2013
[92]
AT2R
minus1332GA
28T2
DMm
icroalbu
minuria
22T2
DMm
acroalbu
minuria
20T2
DMnormoalbum
inuria
and112healthy43ndash6
3yrMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(P
=0016)
Shahsavare
tal2013
[93]
SUMO4163A
G(M
55V)
50T2
DD
Nand50
T2DM
non-DN25ndash45
yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(Plt005)
Arababadi
etal2012
[94]
IL-10minus592C
A100T2
DMnon
-DN100
T2DMD
Nand100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDN
(119875=0001)
Journal of Diabetes Research 11
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2012
[95]
VEG
F+4
05G
C255T2
DMm
icroalbu
minuria
and235T2
DMnon
albu
minuric
50ndash6
7yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersand
albu
minuria(P
=0002)
Rahimietal2012
[96]
MTH
FRA1298C
C677T
ACEID
72T2
DMM
icAlb
68T2
DMM
acAlband72
T2DMnon
-DN46ndash
65yrM
FKe
rmanshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nof
ACED677T(P
=0035)
and
ACED12
98C(P
=0012)
carrierswith
macroalbu
minuria
Rahimietal2012
[97]
eNOSG8
94T
ACEID
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nbetweenAC
EDcarriersand
macroalbu
minuria(P
=0035)
Feleh
garietal2011[98]
ACEID
68T2
DMm
acroalbu
minuria
and72
T2Dmnormoalbum
inuria
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR
Non
significance
Jafarietal2011[99]
eNOSG8
94T
MTH
FRC677TA
1298C
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
eNOST1298
CandeN
OS
T677Tcarrierswith
macroalbu
minuria(Plt005)
(ii)S
ignificantassociatio
nof
eNOSGT+
TTcarrierswith
lipid
profi
le(Plt005)
Rahimietal2011[100]
ACEID
Factor
VLeidenG
1691A
217mean55both
Kerm
anshah
Case
control
PCR
PCR-RF
LPNon
significance
Arababadi2010[101]
IL-4minus590C
T100T2
DMD
Nand150healthy
33ndash4
7yrMF
Rafsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenCT
carriersandDN
(119875lt0001)
Nosratabadi
etal2010
[102]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DMnon
-DN100
T2DMD
Nand
100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandDN
(119875=0012)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandDN
Rahimietal2010
[103]
MTH
FRC677TA
1298C
72T2
DMm
icrolbum
iunira
68T2
DMm
acroalbu
minuria
and72
T2DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
677T1298C
and677T
1298C
carrierswith
macroalbu
minoria
(Plt0001)
(ii)P
ositive
significant
associationof
CT+T
Tand
677T
1298Ccarrierswith
microalbu
minuria(Plt0001)
12 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2009
[104]
ACEID
129T
2DMm
icrolbum
iunira
48T2
DMm
acroalbu
minuria
and145T
2DMnormoalbum
inuria
594plusmn85y
rMF
Tehran
Crosssectio
nal
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
progressionof
albu
minuria
(119875lt001)b
utno
tits
developm
ent
Nikzamiretal2006
[105]
ACEID
85T2
DMD
N85T2
DMnon
-DN
and91
healthy37ndash6
7yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(119875=0006)b
utno
tDN
T2DM
patie
ntsa
ndretin
opathy
Abbasietal2013
[106]
GST
M1n
ullp
ositive
80DRand80
healthy
30ndash70y
rMF
Rasht
Case
control
ARM
S-PC
RNullgenotypes
ignificant
association
Plt005
Dadbinp
oure
tal2013
[107]
(i)GST
M1n
ullp
ositive
(ii)G
STT1nullp
ositive
57DRand58
non-DR
35ndash6
5yrMF
Yazd
Case
control
Multip
lexPC
R
(i)Nullgenotypeo
fGST
M1o
rGST
T1sig
nificantassociatio
n(119875=004)
(ii)N
onsig
nificantassociatio
nof
GST
T1nu
llcarrierswith
DR
Fegh
hietal2011[108]
VEG
F+4
05G
C119
diabeticsw
ithPD
Rand279
diabeticsw
ithNPD
R47ndash6
6yrMF
Ahvaz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersanddiabetic
retin
opathy
(P=0005)
T2DM
patie
ntsa
ndfoot
ulcer
Amolietal2011[109]
(i)VEG
Fminus7C
T(ii)V
EGFminus2578CA
247T2
DM
with
DFU
241
T2DM
with
outD
FUand
98healthy
43ndash6
4MF
Tehran
Case
control
ARM
S-PC
R
(i)Non
significantassociatio
nof
minus7C
Tcarrierswith
DFU
(ii)P
ositive
significant
associationbetweenAAcarriers
andDFU
(P=003)
SNPsin
glenu
cleotid
epo
lymorph
ismT
1DMtype1d
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4T2
DMtype2diabetes
mellitusP
CRp
olym
erasechainreactio
nRF
LPrestrictio
nfragmentlengthpo
lymorph
ismILinterle
ukinSS-PC
Rsequ
ence
specificP
CRV
DR
vitamin
DreceptorT
AP2
transpo
rter
2AT
P-bind
ingcassetteA
RMS-PC
Ram
plificatio
nrefractory
mutationsyste
mPC
RPC
R-SSPPC
Rsin
glespecificprim
erT
GF120573
transform
inggrow
thfactor120573D
Md
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4
MODY
maturity
onsetd
iabeteso
fthe
youn
gHNF-
1120572h
epatocytenu
clear
factor
1120572M
VCm
icrovascular
complicationsT
CF7L
2transcrip
tionfactor
7-lik
e2PC
R-SSCA
PCR
singlestr
andconformationpo
lymorph
ismanalysis
ER120572estr
ogen
receptor120572N
D
nond
iabeticsTC
totalcholesterolTG
trig
lycerid
esP
PAR-1205742peroxisomep
roliferator-activates
receptor120574G
LP-1R
glucagon
-like
peptid
1receptorAPO
apo
lipop
roteinC
XCL5chemokineC
-X-C
motifligand
5SD
F-1120573stro
malderiv
edfactor-1120573IRS
1amp2insulin
receptor
substrate1amp
2GSTglutathione-S-tr
ansfe
raseSLC
30A8solublecarrier3
0A8KC
NJPo
tassium
inwardly-rectify
ingchanneleN
OSendo
thelial
nitricoxidesynthaseVNTR
variablen
umbero
ftandem
repeatsEN
PP1ectoenzymen
ucleotidep
yrop
hosphateph
osph
odieste
rase1SU
MOsmallubiqu
itin-lik
emod
ifier4UCP
2un
coup
lingp
rotein
2MTH
FR
methylenetetrahydrofolateredu
ctaseIFN120574interferon120574C
CR5C-
Cchem
okiner
eceptortype5
INSR
insulin
receptorC
SGE
conformation-sensitive
gelelectroph
oresis
ACE
angiotensin
Icon
vertingenzyme
HFE
hem
ochrom
atosisgenePTP
N1proteintyrosin
Phosph
atase1B
CADcoron
arya
rteryd
iseaseCE
TPcho
leste
ryleste
rtransferp
roteinA
T1R
angiotensin
IreceptorMMP3
matrix
metalloproteinase
3CA
Scoronary
artery
steno
sisB
ChEK
Butyrylcho
linesteraseK
DNdiabetic
neph
ropathyAT
2Rang
iotensin
IIreceptorV
EGFvascularepith
elium
grow
thfactorD
Rdiabeticretin
opathy
PDR
proliferativ
ediabetic
retin
opathy
NPD
Rno
n-PD
RDFU
diabetic
foot
ulcer
Journal of Diabetes Research 13
321 T1DM Related Genes All the studies in this subgroupincluding 12 studies [22ndash33] were in a case control studydesign using PCR (polymerase chain reaction) [33] PCR-RFLP (restriction fragment length polymorphism) [22 2325 26 32] PCR-SSP (single specific primer) [24 28ndash32]and ARMS-PCR (amplification refractory mutation systemPCR) [27] method In all studies both men and women wereincluded and the overall 2519 subjects were under 40 yearsold
Association of interleukins including IL-18 (interleukin)and IL-12 with T1DM revealed that the minus137CG polymor-phism of IL-18 had significant association with T1DM (119875 =0037 119875 = 00001) while no significant relation was observedbetween minus607AC variant of this gene and T1DM [24 28]Investigating IL-12 also showed that there was a significantassociation between +1188AC polymorphism of this geneand T1DM (119875 = 0035) [30]
In 2 studies the association of +49AG variant of CTLA-4 (cytotoxic T lymphocyte associated antigen 4) was investi-gated and it was revealed that there was a positive significantassociation between AG genotype and T1DM (119875 = 001 119875 lt0001) [22 32] One of these studies also revealed that therewas a negative relation betweenAA genotype and T1DM [32]
Vitamin D receptor (VDR) was investigated in 2 studies[25 26] Both of them assessed the association of FokI BsmIApaI and TaqI variants of VDR with T1DM In one studywhichwas performed on 114 subjects Aa (119875 = 0003) FF (119875 =0008) and Bb (119875 = 0014) genotypes were shown to be pos-itively associated with T1DM but no significant associationwas observed between TaqI polymorphism and T1DM [25]Another study which was performed on 187 subjects showedno significant association between T1DM and FokI BsmIand ApaI However TT genotype was observed to be morefrequent in controls (119875 = 0007) and negatively associatedwith T1DM [26]
Different polymorphisms of TAP2 and their associationwith T1DM were investigated in 191 subjects It was shownthat Ile379Val and Stop687Gln had significant associationwith T1DM (119875 = 0001 and 119875 = 0013 resp) Other variantsof TAP2 (transporter 2 ATP-binding cassette) includingAla565Thr Arg651Cys and Ala665Thr were not associatedwith T1DM significantly [27]
Association of alleles A2ndashA9 of CD4 with T1DM wasassessed in 200 subjects It was revealed that A3 allele hadnegative (119875 = 0025) and A5 had positive (119875 = 0001)significant association with T1DM [33]
Association of some other genes including osteopontin(rs1126772 polymorphism) integrin 1205724 (rs1449263 polymor-phism) CD44 (rs8193 polymorphism) and TGF120573 (trans-forming growth factor) (+915CG polymorphism) was alsoinvestigated in 2 studies and no significant relation wasobserved between these variants and T1DM [23 29]
322 MODY In this category only one study was found [34]and the association of Val255Met polymorphism of HNF120572and diabetes was investigated in 101 subjects includingMODY subjects their relatives and healthy controls [34]Thestudy was designed as a case control association study andPCR-RFLP and direct sequencing was used for genotyping
of variants Val255Met mutation in this investigation wasobserved in MODY subjects and their relatives but not incontrol group
323 T2DM Related Genes In this subgroup 42 studieswere assessed and all of them were designed as case controlassociation studies [22 35ndash68 70ndash75] except for one whichwas cross sectionally designed [69] In 33 studies PCR- RFLPwas used for genotyping [22 36ndash38 40ndash54 56 58ndash61 63ndash66 69 72ndash75] In 5 of them PCR was used [35 57 62 70 71]and the remaining studies PCR-SCA [39] real-timePCR [55]ARMS-PCR [66] Gap PCR [67] and CSGE (conformation-sensitive gel electrophoresis) sequencing [68] as the genotyp-ing method were applied
Association between two polymorphisms of TCF7L2including rs7903146 (CT) and rs12255372 (GT)was assessedin three studies [38 48 53] In one study investigatingrs7903146 (CT) in 466 subjects significant difference in thefrequency of CC and CT genotypes was observed betweenT2DM and control group (119875 = 0045) [38] However inanother study this polymorphism showed a positive signifi-cant associationwith TT genotype in T2DM (119875 = 0008) [53]Investigation of rs12255372 (GT) polymorphism of TCF7L2in another study showed that among 491 subjects there wasa positive significant association between TT carriers andT2DM (119875 = 0014) [48]
Investigating the association of calreticulinwith T2DM in650 subjects showed two mutations only in case group 9 bpdeletion of 397ndash399 codons and GgtT mutation at IVSII-142[39]
Association of estrogen receptor 120572 and its PvuII(PPPppp) and XbaI(XXXxxx) polymorphism with T2DM intwo studies was assessed [40 49] In one study the significantassociation of PvuII and XbaI polymorphisms with T2DMwas observed (119875 = 0014 and 119875 = 0002 resp) [40] Inanother study it was revealed that pooled Pp+pp and XX+xxmale carriers have positive significant associationwithT2DM(119875 = 0001 and 119875 = 0026 resp) [49]
Association of Pro12Ala polymorphism of PPAR120574 withT2DMwas investigated in three studies [41 69 75] Negativesignificant association of AlaAla genotype with T2DM wasobserved in two studies (119875 = 0003) [41 75] AlaPro carrierswere shown to be positively associated in one study [41] andnegatively associated in another study [75] with T2DM (119875 lt0001 and 119875 = 0003 resp) However in the third studyno significant association was observed between Pro12Alapolymorphism of PPAR120574 and T2DM [69]
Association of different polymorphisms of ApoAI withT2DM was investigated in two studies [43 72] In one studyinvestigation of MSPI polymorphism showed no significantassociation with T2DM [43] In another study it was shownthat G-75A polymorphism of ApoAI was not associated withT2DM while a significant association was found betweenC+83T polymorphism and T2DM (119875 = 0028) [72]
Two studies assessed the association of minus156GgtC poly-morphism of CXCL5 with T2DM [44 65] In one studypositive significant association of GC carriers (119875 = 0006)and negative association of GG carriers (119875 = 001) was foundbetween diabetic patients and healthy controls [44] and
14 Journal of Diabetes Research
in another study positive significant association was foundbetween GC or CC carriers and T2DM (119875 = 0009) [64]
Adiponectin and its association with T2DM were inves-tigated in two studies [56 73] In one study two variantsincluding +45TG and minus11391GA were investigated but nosignificant relation was found between these two polymor-phisms and T2DM [56] However in another study investi-gating +45TG polymorphism of adiponectin it was revealedthat nonobese T2DM subjects had significantly higher TTgenotype (119875 = 004) [73]
In one study that investigated insulin receptor gene thefollowing mutations were found only in T2DM 511CgtA514TgtG 586 and 628TgtA on exon 2 694GgtC 680GgtA onexon 3 1627AgtT on exon 8 ATgtTG on intron 9 2007CgtCTon exon 9 2595CgtCT and 2669GgtCG on exon 13 2706 and2717CgtG 2752CgtT and 2753CgtG on exon 14 and 3471TgtAand 3516TgtG on exon 19 These mutations were not seen incontrol subjects [68]
Other variants which had significant association withT2DM included haptoglobin (allele 2-2) leptin (G-2548Apolymorphism) paraoxonase 2 (Ser311Cys polymorphism)GST (glutathione-S-transferase) M1 and GSTM1GSTT1interaction calpain-10 (SNP (single nucleotide polymor-phism) 43) IRS-1 (G972R polymorphism) and IRS-2(G1057D polymorphism) VDR (vitamin D receptor) (TaqIpolymorphism) KCNJ11 (E23K polymorphism) eNOS(endothelial nitric oxide synthase) VNTR (intron 4 ab pol-ymorphism) resistin (minus420CG polymorphism) and ACE(InsertionDeletion) [35ndash37 45 47 50 55 57 58 64 70]
In contrast to above variants CTLA4 (+49AG poly-morphism) HNF-1120572 (Ala98Val polymorphism) GLP-1R(glucagon-like peptid 1 receptor) (Thr149Met polymor-ohism) SLC30A8 (Arg325Trp polymorphism) GSTP1(Ile105Val polymorphism) glucokinase (minus30GA polymor-phism) SDF-1120573 (stromal derived factor -1 120573) (G801A poly-morphism) ApoE (apolipoprotein E) ENPP1 (ectoenzymenucleotide pyrophosphate phosphodiesterase 1) (K121Q poly-morphism) SUMO4 (small ubiquitin-like modifier 4)Met55Val polymorphism) MTHFR (C677T polymorphism)UCP2 (uncoupling protein 2) (minus866GA polymorphism)5HTTLPR IL-4 (minus590CT polymorphism) IFN-120574 (inter-feron 120574) (+874TA polymorphism) CCR5 (C-C chemokinereceptor type 5) (12057532mutation) HFE (hemochromatosisgene) (H63D C282Y PTPN1 (protein tyrosin Phosphatase1B)minus51delA minus451AgtG minus467TgtC minus1023CgtA minus1045GgtAminus1286 3 bp del ACA minus1291 9 bp del CTAGACTAA poly-morphisms) were not significantly associated with T2DM[22 42 46 50ndash52 54 59ndash63 66 67 71 74]
324 Genes Related to Insulin Resistance In this subgroupfour studies were assessed and all were designed as case-control association studies Three studies used PCR-RFL [7678 79] and one study used real-time PCR [77] for genotyping
The studies assessed in this subgroup showed a positiveassociation of TG carriers of +45TG polymorphism ofadiponectin (119875 = 0032) and Ala allele carriers of Pro12Alapolymorphism of PPAR120574 (119875 = 0036) with T2DM [76 77]A positive significant association of ff carriers of VDR wasalso shown (FokI polymorphism) (119875 = 002) and negative
association of 148insG carriers of PTPN1 (148insG polymor-phism) (119875 = 0041) with insulin resistance index [7879] However no significant association was shown betweenadiponectin receptor-2+795GA and T2DM [76]
325 Genes Related to Cardiovascular Disease in DiabetesDesign of all 11 studies in this subgroup was case-controlassociation study [80ndash84 86ndash90] except one study which wasdesigned as cross sectional [85] PCR-RFLP was used in all ofthem for genotyping [80ndash88 90] except in one study whichused ARMS-PCR method [89]
Paraoxonase 1 (163TA polymorphism) was the only vari-ant in this subgroup which was not significantly associatedwith atherosclerosis risk in T2DM [80] Investigation ofanother polymorphism of Paraoxonase 1 (Q192R) revealedthat diabetics with CAD had significant increase in RRgenotype (119875 lt 005) [81]
Investigating B1 and B2 alleles of CETP TaqI B allele in400 subjects showed that pooling of B1B1+B1B2 and B1B1genotypes had significant association with T2DM and CAD(119875 lt 001) On the other hand assessing the G894T poly-morphism of eNOS showed positive significant associationbetween TG and TT carriers and CAD (119875 lt 005) It was alsoshown that concomitant presence of NOS3 T allele and CEPTB1 allele was significantly associated with T2DM (119875 = 0004)and CAD (119875 = 0002) [83]
Investigation of apolipoprotein E (E2 E3 and E4) allelesshowed the association of E2 and E4 alleles with CAD(119875 lt 0001) [84 87] Also it was shown that interactionof butyrylcholinesterase (BChE K) and apolipoprotein E(ApoE) was associated significantly with CAD and diabetesApoE4BChE K had significant association with lipid profilesas well (119875 lt 005) [87]
Adiponectin +276GT and +45TG were significantlyassociated with CAD (119875 = 0023 and 0033 resp) [82] whileinvestigating minus1612 5A6A polymorphism of MMP-3 (matrixmetalloproteinase 3) showed a significant association withCAS (coronary artery stenosis) (119875 = 0008) [86]
In addition A1166C polymorphism of AT1R (angiotensinI receptor) and minus420CG polymorphism of resistin in dia-betic patients with CAD revealed significant association withdiabetes 119875 = 001 and 119875 = 0009 respectively [84 85]
Another study showed insertion(I)deletion(D) polymor-phismof angiotensin converting enzyme (ACE)DDgenotypewas significantly associated with higher blood pressure (119875 =0026) [89]
Factor V Leiden (G1691A polymorphism) prothrombin(G20210A polymorphism) and MTHFR (methylenetetrahy-drofolate reductase) (C677T polymorphism) were the vari-ants which were not significantly associated with CAD andT2DM in this subgroup [88]
326 Genes Related to Diabetic Nephropathy All of 15 studiesin this subgroup were designed as case-control associationstudies [91ndash106] In 7 studies PCR-RFLP was used forgenotyping [92ndash95 99 102 103] in four studies PCRwas used[98 101 104 105] and in 4 of them both PCR and PCR-RFLPwere used [91 96 97 100]
Journal of Diabetes Research 15
Studying the association of 163AG polymorphism ofSUMO4 showed a positive significant association betweenAA carriers and diabetic nephropathy (119875 lt 005) [93]
Studying the interaction of eNOS4ab and G894Trevealed positive significant association between 4a or 894Tallele carriers and macro- and microalbuminuria (119875 = 001119875 = 002 resp) [91] It was observed that the interaction ofeNOS (G894T polymorphism) andACE (ID alleles) was sig-nificantly associated with more frequent macroalbuminuria(119875 = 0035) [97]
It has also been shown that interaction of eNOS (G894Tpolymorphisms) and MTHFR (C677T and A1298C poly-morphisms) eNOS T1298 C and eNOS T677 T carriershad positive significant association with macroalbuminuriaIn addition significant association of eNOS GT+TT carrierswith lipid profile (119875 lt 005) was shown in this study [99]
C677T andA1298C polymorphisms ofMTHFRwere alsoinvestigated in another study revealing that 677T 1298Cand 677T1298C carriers were significantly associated withmacroalbuminuria (119875 lt 0001) Positive significant asso-ciation when pooling CT+TT genotypes and 677T1298Cwas also found with microalbuminuria (119875 lt 0001) [103]Investigating the interaction of MTHFR (A1298C C677Tpolymorphisms) and ACE (ID alleles) showed a positivesignificant association of ACE D677T (119875 = 0035) and ACED1298C (119875 = 0012) genotypeswithmacroalbuminuria [96]
ACE (ID alleles) polymorphisms were investigated inthree studies In one study positive significant association(119875 lt 001) between DD carriers and progression but notdevelopment of albuminuria was observed [104] In anotherstudy in nephropathic subjects association of DD carriersand T2DM (119875 = 0006) but not nephropathy was revealed[105] However another study did not show significant asso-ciation of ACE with macroalbuminuria [98] Interaction ofACE (ID alleles) with Factor V Leiden (G1691A polymor-phism) was not significant [100]
Association of interleukins including IL-4 and IL-10 withdiabetic nephropathy was also investigated in two studiesStudy of minus592CA polymorphism of IL-10 revealed positivesignificant association between CC carriers and nephropathy(119875 = 0001) [94] and study ofminus590CTpolymorphismof IL-4revealed positive significant association between CT carriersand nephropathy (119875 lt 0001) [101]
Other significant associations between variants and dia-betic nephropathy included AT2R (angiotensin II recep-tor) (minus1332GA polymorphism) VEGF (vascular epitheliumgrowth factor) (+405GC polymorphism) and VDR (TaqIpolymorphism) [92 95 102] ApaI polymorphism of VDRwas not significantly associated with diabetic nephropathy[102]
327 Genes Related to Diabetic Retinopathy All of the 3studies in this subgroup were conducted as case-controlassociation studies [106ndash108]
Investigating nullpositive genotype of GSTM1 in a studywhich used ARMS-PCR for genotyping revealed that nullgenotype is significantly associated with diabetic retinopathy(119875 lt 005) [106] This result was confirmed in another study
by using multiplex PCR as genotyping [107] although nosignificant association between GSTT1 and retinopathy wasfound in this study [107]
Investigating +405GC polymorphism of VEGF alsorevealed positive significant association between GG carriersand diabetic retinopathy (119875 = 0005) [108]
328 Genes Related to Diabetic Foot Ulcer In this subgrouponly one study was found [109] which was case-controldesigned and used ARMS-PCR for genotyping In this studyassociation of minus7CT and minus2578CA polymorphisms ofVEGF with diabetic foot ulcer (DFU) was investigated and apositive significant association betweenAA carriers andDFU(119875 = 003) was observed But no significant association wasfound between minus7CT of VEGF and DFU [109]
4 Discussion
Diabetes mellitus is the eighth most frequent disease leadingcause of death throughout the world and now ranks the fifthfollowing communicable diseases cardiovascular diseasecancer and injuries [110] Prevalence of diabetes mellitus isincreasing worldwide [6]
Type 2 diabetes is the most frequent type of diabetesmellitus [110 111] Multiple genes and environmental factorsaffect the prevalence of T2DM Systematic review and meta-analysis studies have assessed the association between dif-ferent genes and T2DM Glutathione-S-transferase includingGSTMI GSTM1 and GSTP1 are important genes and theirassociation with diabetes has been investigated in two meta-analysis studies [112 113] It was revealed that null genotypeof both GSTM1 and GSTT1 could be as a risk factor fordiabetes while no significant association was found betweenGSTP1 and diabetes [112 113] These results are in linewith our finding and confirming the association of the nullgenotype of GSTT1 and GSTM1 with T2DM in Iranianpopulation [50] The relation between GSTT1 and GSTM1and diabetic retinopathy has also been shown in Iranianpopulation [106 107]
MTHFR is another important gene in association withT2DM and other related complications No associationof C677T polymorphism of MTHFR gene was found inAfricans Asians and Caucasians [114] MTHFR is a genewhich is involved in DNA methylation and synthesis andregulated folate activity It has been reported that mutanthomozygote and heterozygote of C677T polymorphism ofMTHFR increase plasma homocysteine which is an impor-tant factor leading to diabetic nephropathy (DN) and as aresult C677T polymorphism of MTHFR can be associatedwith the development of DN In Caucasians this associationhas also been observed [115] In Iranian population in linewith other populations no significant association was foundbetween MTHFR polymorphisms and T2DM [63] althoughsignificant association of 677T and 1298C alleles with diabeticnephropathy was observed [87] Interaction of two polymor-phisms and also interaction of MTHFR polymorphisms withother genes such as ACE and eNOS showed an associationwith development of DN [96 99]
16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Journal of Diabetes Research 3
Iden
tifica
tion
Records identified through
Scre
enin
gEl
igib
ility
Inclu
ded
Eligible full texts records
Included records to systematic
database searching (n = 3029)
Records excluded by title (n = 2734)
- Excluded due to duplicatepublication (n = 106)
(n = 104)
review (n = 88)
Records excluded by full text (n = 16)
- Excluded due to data from the samepopulation (n = 13)
- Excluded due to not measuredrelevant outcomes (n = 3)
- Google scholar (n = 2000)
- PubMed (n = 300)
- Scopus (n = 557)
- Persian web databases (n = 172)
- Excluded by abstract (n = 85)
Figure 1 Flow diagram of study selection process
as case-control cohort or cross sectional According toWHO criteria diabetes mellitus was defined as FBS ge7mmolL (126mgdL) or 2 h plasma glucose ge111mmolL(200mgdL) [20] In addition we excluded animal studiesclinical trials short communications letters to editor disser-tations in vitro studies review articles and population-basedstudies conducted in pregnant women Two researchers SEand MKH independently reviewed title abstract and fulltext of each article to assess the eligible articles according toinclusion and exclusion criteria Inclusion and exclusion ofarticles were supervised by a third reviewer (OTM) in case ofconflicts There was no limitation for language
23 Data Extraction and Quality Assessment The follow-ing data were extracted and presented in an excel sheetauthor(s) year genes and SNPs patientsrsquo characteristics(sample size age and sex) city study design genotypingmethod and significant association Six selected items fromthe STROBE (strengthening the reporting of observationalstudies in epidemiology) checklist [21] was used for qualityassessment of the included studies and assessed separatelyfor each included article The below items were considered(a) clearly define the outcome and association between genevariants and diabetes (b) give the eligibility criteria (c)present key elements of study design (d) report numbers orsignificancenonsignificance statistically of outcome events(e) give characteristics of study participants and (f) describethe locations and relevant dates All studies with quality scorege3 were considered as high quality study and included in oursystematic review
24 Data Synthesis and Analysis Due to heterogeneity ingenotyping techniques and also differences in genetic variantsstudied in assessed included articles performing a meta-analysis was impossible
3 Results
31 Search Results A summary of the literature reviewprocess performed in this study is presented in a flow chartin Figure 1 In final step 88 eligible studies were includedin this study and assessed due to the inclusionexclusioncriteria [22ndash109] Table 1 shows the summary of each includedinvestigation
32 Studies Characteristics Overall 27396 diabetics andhealthy subjects were studied in this systematic review Allof the subjects were recruited from total urban populationT2DMwas themost investigated type of diabetes (42 studies)[22ndash75] Among diabetes complications diabetic nephropa-thy and CAD were the most examined respectively [80ndash105] Twelve studies were carried out on T1DM [22ndash33]The least investigated complication was diabetic foot ulcerwhich was assessed only in one study [109] Retinopathyand insulin resistance were also among the least investigatedcomplications including 3 and 4 studies respectively [76ndash79 106ndash108] Only one study assessed MODY in our review[34] All of the studies were performed on both gendersexcept for one which was performed on males [45]
Details of the included studies are described as below
4 Journal of Diabetes Research
Table1Ch
aracteris
ticso
fincludedarticlesinsyste
maticreview
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
T1DM
andcomplications
Ahm
adietal2013
[22]
CTLA
-4+49AG
60T1DM56T2
DMand
107
healthymale(M)female(F)
Kurdistan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAG
carriersandT1DM
(P=001)
Karamizadeh
etal2013
[23]
(i)Oste
opon
tinrs11
26772
(ii)Integrin1205724rs1449263
CD44
rs8193
87T1DM
and86
healthy
lt20
yrM
FSh
iraz
Case
control
PCR-RF
LPNon
significance
Rahb
ani-N
abar
etal2013
[24]
IL-18minus137C
G104T1DM
and92
healthy
9ndash32
yrM
FTabriz
Case
control
SS-PCR
Positives
ignificantassociatio
nbetweenGGcarriersandT1DM
(P=0037)
Bonakd
aran
etal2012
[25]
(i)VDRFokI
(FFFfff
)(ii)B
smI(BB
Bbbb)
ApaI
(AA
Aaaa)
(iii)TaqI
(TTTttt)
69T1DM
and45
healthy
lt35
yrM
FMashh
adCa
secontrol
PCR-RF
LP
Positives
ignificantassociatio
nbetweenAa(
P=0003)FF
(P=0008)and
Bb(P
=0014)
carrierswith
T1DMsignificant
associationbetweenffgeno
type
andhisto
ryof
ketoacidosis
(P=004)
Moh
ammadnejadetal2012
[26]
(i)VDRTaqI
(TTTttt)
(ii)V
DR
FokIB
smIAp
aI87
T1DM
and100healthy
17ndash38y
rMF
Mashh
adCa
secontrol
PCR-RF
LP
(i)Negatives
ignificant
associationbetweenTT
carriers
andT1DM
(P=0007)
(ii)N
onsig
nificance
association
betweenotherc
arrie
rsof
VDR
andT1DM
Afsharietal2011[27]
(i)TA
P2Ile379Va
l(ii)T
AP2
Stop687Gln
(iii)TA
P2Ala565Th
rArg651Cy
sAla665Th
r
87T1DM
and104healthy
lt30
yrM
FMashh
adCa
secontrol
ARM
S-PC
R
(i)Sign
ificant
association
betweenIle
379V
alandT1DM
(P=0001)
(ii)S
ignificantassociatio
nbetweenStop
687G
lnandT1DM
(P=0013)
(iii)Non
significantassociatio
nbetweenotherc
arrie
rsof
TAP2
andT1DM
Massoud
etal2009
[28]
(i)IL-18minus137C
G(ii)IL-18minus607A
C75
T1DM
and88
healthy
lt30
yrM
FTehran
Case
control
PCR-SSP
(i)Po
sitives
ignificantassociatio
nbetweenGGcarriersandT1DM
(P=000
01)
(ii)S
ignificantassociatio
nbetweenCC
geno
type
with
T1DM
(P=000
01)
(iii)Non
significance
association
betweenotherc
arrie
rsof
IL-18
andT1DM
Journal of Diabetes Research 5
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Masou
detal2007
[29]
TGF120573
+915C
G75
T1DM
and88
healthy
lt30
yrM
FTehran
Case
control
PCR-SSP
Non
significance
Masou
detal2007
[30]
IL-12+1188A
C75
T1DM
and88
healthy
lt30
yrM
FTehran
Case
control
PCR-SSP
Sign
ificant
associationbetween
AAandAC
geno
type
andT1DM
(P=0035)
Mojtahedi
etal2006
[31]
IL-18minus607A
C
minus137C
G112T1DM
and194no
n-DM
lt15
andgt15yrM
FSh
iraz
Case
control
PCR-SSP
minus137C
Candminus607A
Aminus137C
Csig
nificantassociatio
nwith
T1DM
inon
setgt
15yr
(P=0027)
Mojtahedi
etal2005
[32]
CTLA
-4+49AG
109T1DM
and331h
ealth
y0ndash
37yrM
FSh
iraz
Case
control
PCR-SSP
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenAG
carriersandT1DM
(P=000)
(ii)N
egatives
ignificant
associationbetweenAAcarriers
andT1DM
(P=000)
Zamanietal2005
[33]
CD4A2
ndashA9
92T1DM
and108healthy
gt35
yrM
FTehran
Case
control
PCR
Negatives
ignificantassociatio
nbetweenA3alleleandT1DM
(P=0025)
Positives
ignificantassociatio
nbetweenA5alleleandT1DM
(P=0001)
MODY
Tagh
avietal2009
[34]
HNF120572
Val255M
et30
MODY21
relativ
esand
50healthy25ndash35y
rMF
Mashh
adCa
secontrol
PCR-FL
Psequ
encing
Them
utationwas
foun
din
patie
ntsa
ndrelatives
butn
otin
controls
T2DM
andcomplications
Ahm
adietal2013
[22]
CTLA
-4+49AG
Said
above
Said
above
Said
above
Said
above
Non
significance
Amiri
etal2013
[35]
Haptoglob
in1-
12-12-2
134T2
DM
with
MVC
s71
T2DM
with
outM
VCs
46ndash72y
rMF
Sari
Case
control
PCR
Hp2-2
high
lysig
nificantfor
T2DM
(P=005)
And
alib
etal2013
[36]
Paraoxon
ase2
Ser311Cys
100T2
DM
and100healthy
51yrM
FIsfahan
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
CysCy
sand
CysSerc
arrie
rsand
negativ
esignificantassociatio
nof
SerSerc
arrie
rswith
T2DM
(Plt005)
Kohanetal2013
[37]
LeptinG
-2548A
100T2
DM
and100healthy
44ndash6
6yrMF
Arsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersandT2
DM
(P=000
4)
Alamietal2013
[38]
TCF7L2
rs7903146
(CT)
233T
2DM
and233controls
gt40
yrM
FGorgan
Case
control
PCR-RF
LPCC
andCT
geno
typessignificant
differenceb
etweenT2
DM
and
controls(P
=0045)
Mahmazietal2013
[39]
Calre
ticulin
120T2
DM
and530controls
43ndash6
6yrMF
Zanjan
Case
control
PCR-SC
A9b
pdeletio
nof
397ndash399codo
nsGgtTmutationatIV
SII-142in
T2DM
notincontrols
6 Journal of Diabetes ResearchTa
ble1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Moh
ammadietal2013
[40]
(i)ER120572PvuII(PPPp
pp)
(ii)E
R120572XbaI(XX
Xxxx)
174T2
DM
and174ND
35ndash6
5yrMF
Jahrom
Case
control
PCR-RF
LP
(i)Sign
ificant
associationwith
T2DM
(P=0014)
TC(P
=0007)and
TG(119875=0005)fem
alec
arrie
rs(ii)S
ignificantassociatio
nwith
T2DM
(119875=0002)TC
(119875=0003)andTG
(119875=0009)
femalec
arrie
rs
Motavallianetal2013
[41]
PPAR-1205742Pro12A
la100T2
DM
and100healthy
51yrM
FIsfahan
Case
control
PCR-RF
LP
Negatives
ignificantassociatio
nbetweenAlaA
lacarriers
(119875lt0001)a
ndpo
sitive
significantassociatio
nbetween
AlaPro
carrierswith
T2DM
(119875lt0001)
Sepahi
etal2013
[42]
HNF-1120572Ala98Va
lGLP
-1RTh
r149Met
100T2
DM
and50
healthy
controlsle35
andgt35
yrM
FMashh
adCa
secontrol
PCR-RF
LPNon
significance
Sheikh
haetal2013
[43]
APO
A1M
SP-I
200T2
DM
and200healthy
418yrM
FYazd
Case
control
PCR-RF
LPNon
significance
Yagh
oubietal2013
[44]
CXCL
5minus156GgtC
100T2
DM54y
rand
100healthy
56yrM
FArdabil
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GCcarriers(119875=0006)a
ndnegativ
esignificantassociatio
nof
GGcarrierswith
T2DM
(P=001)
Bahreini
etal2012
[45]
Calpain-10SNP4
3(AG)
102T2
DM
and100healthy
40ndash70y
rM
EastAzerbayjan
Case
control
PCR-RF
LPGallelea
srisk
factor
ofT2
DM
(P=0037)
Derakhshanetal2012
[46]
SDF-1120573G
801A
200T2
DM
and200healthy
40yrM
FRa
fsanjan
Case
control
PCR-RF
LPNon
significance
Haghani
etal2012
[47]
(i)IRS-1G
972R
(ii)IRS
-2G
1057D
336T2
DM
and341h
ealth
y44
ndash63y
rMF
Ilam
andKe
rmanshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
GR(P
=0001)andRR
(119875=00001)carrie
rswith
T2DM
(ii)P
ositive
significant
associationbetweenGDcarriers
andT2
DM
(P=0016)
Alamietal2012
[48]
TCF7L2
rs12
255372
(GT)
236T2
DM
and255healthy
gt37
yrM
FGorgan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersandT2
DM
(P=0014)
Meshk
anietal2012
[49]
(i)ER120572PvuII(PPPp
pp)
(ii)E
R120572XbaI(XX
Xxxx)
155T2
DM
and377controls
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
pooled
Pp+pp
malec
arrie
rs(P
=0001)with
T2DM
(ii)P
ositive
significant
associationof
pooled
XX+
xxmalec
arrie
rs(P
=0026)
with
T2DM
Journal of Diabetes Research 7
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Moasser
etal2012
[50]
GST
M1p
resentnull
GST
T1presentnull
GST
P1Ile105Va
l
171T
2DM
and169healthy
25ndash6
5yrMF
Shira
zCa
secontrol
PCR-RF
LP
GST
M1-n
ull(P=0016)
and
interactionof
GST
M-nullG
STT1-null
(119875=0022)significant
associationwith
T2DM
Moh
addese
tal2012
[51]
SLC3
0A8Arg325Trp
125T2
DM
and125controls
40ndash70y
rMF
Azarbayjan
Case
control
PCR-RF
LPNon
significance
Oladi
etal2012
[52]
Glucokinaseminus30GA
542subjects
18ndash6
5yrMF
Mashh
adCr
osssectio
nal
PCR-RF
LPNon
significance
Palizbanetal2012
[53]
TCF7L2
rs7903146
(CT)
110T2
DM
and80
healthy
46ndash6
7yrMF
Isfahan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersandT2
DM
(P=0008)
Tabatabaei-M
alazyetal2012
[54]
ApoE
E3-E3
E2-E3
E4-E3
156T2
DM
and155healthy
25ndash6
5MF
Tehran
Case
control
PCR-RF
LPNon
significance
Ghasemietal2012
[55]
KCNJ11
E23K
358T2
DM
and388healthy
41ndash6
9yrMF
Rasht
Case
control
Realtim
ePCR
Positives
ignificantassociatio
nbetweenKK
carriersandob
ese
T2DM
(P=0037)
Ranjbare
tal2011[56]
Adipon
ectin
+45TG
minus113
91GA
244T2
DM
and99
healthy
37ndash6
5yrMF
Rafsanjan
Case
control
PCR-RF
LPNon
significant
Mehrab-Moh
seni
etal2011[57]
eNOSVNTR
intro
n4ab
220T2
DM
and96
healthy
53plusmn15yrM
FRa
fsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenaa
orab
carriersand
T2DM
(P=002)
Nosratabadi
etal2011[58]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DM
and100healthy
40yrM
FRa
fsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandT2
DM
(Plt0001)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandT2
DM
Saberietal2011[59]
ENPP
1K121Q
155T2
DM
and377healthy
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LPNon
significance
Fallahetal2010
[60]
SUMO4Met55Va
l(16
3AG
)50
T2DM
and50
healthy
25ndash4
5yrMF
Tehran
Case
control
PCR-RF
LPNon
significance
Heidarietal2010
[61]
UCP
2minus866G
A75
T2DM75NDob
esea
nd75
NDno
nobese35ndash76
yrM
FTehran
Case
control
PCR-RF
LPNon
significance
Nazem
etal2010
[62]
5HTT
LPRSSSLLL
90T2
DM
and90
healthy
54ndash6
6yrMF
Shira
zCa
secontrol
PCR
Non
significance
Bazzaz
etal2010
[63]
MTH
FRC677T
401T
2DM74NDob
esea
nd207
NDno
nobese30ndash
63yrM
FTehran
Case
control
PCR-RF
LPNon
significance
Emam
gholipou
retal2009
[64]
resistin
minus420C
G47
T2DM
and66
healthy
58plusmn9y
rMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandT2
DM
(P=000
9)
Hasani-R
anjbar
etal2009
[65]
CXCL
5minus156G
C230T2
DM
and120healthy
40ndash6
3yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGCor
CCcarriersand
T2DM
(P=000
4)
8 Journal of Diabetes ResearchTa
ble1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
KazemiA
rababadi
etal2009
[66]
IL-4minus590C
TIFN-120574+874T
A160T2
DM
and160healthy
38plusmn9y
rMF
Rafsanjan
Case
control
PCR-RF
LPARM
S-PC
RNon
significance
Arababadi
etal2009
[67]
CCR5
12057532mutation
200T2
DM
and300healthy
40plusmn9y
rMF
Rafsanjan
Case
control
Gap-PCR
Non
significance
Kazemietal2009
[68]
INSR
128T2
DMgt
40yrM
FTehran
Case
control
PCR
CSGE
sequ
encing
Follo
wingmutations
werefou
ndon
lyin
T2DM
511CgtA514Tgt
G586and
628TgtAon
exon
2694GgtCand680GgtAon
exon
31627AgtTon
exon
8ATgtTG
onintro
n9
2007Cgt
CTon
exon
92595Cgt
CTand2669GgtCGon
exon
132706
and2717Cgt
G2752CgtT
2753Cgt
Gonexon
143471Tgt
Aand3516Tgt
Gon
exon
19
Mirz
aeietal2009
[69]
PPAR120574
2Pro12A
la78
norm
al78ob
ese78
T2DM
and78
obeseT
2DM25ndash64
yr
MF
Tehran
Crosssectio
nal
PCR-RF
LPNon
significance
Nikzamiretal2008
[70]
ACEinsertion(I)
deletion(D
)170T2
DM
and144healthyMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(P=002)
Sharifi
etal2008
[71]
HFE
H63D
C282Y
101T
2DM
and101h
ealth
y55plusmn11yrM
FZa
njan
Case
control
PCR
Non
significance
Besharatietal2007
[72]
(i)Ap
oA-IG
-75A
(ii)A
poA-
IC+8
3T215subjects26ndash
64yrM
FTehran
Crosssectio
nal
PCR-RF
LP
(i)Non
significantassociatio
nbetweenG-75A
carriersand
T2DM
(ii)P
ositive
significant
associationbetweenCT
carriers
andT2
DM
(P=0028)
Hasani-R
anjbar
etal2007
[73]
Adipon
ectin
+45TG
80T2
DM
obese72
T2DM
nono
beseand
70healthy
25ndash6
4yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersand
nono
bese
T2DM
(P=004)
Meshk
anietal2007
[74]
PTPN
1minus51delA
minus451AgtGminus467TgtC
minus1023Cgt
Aminus1045GgtAminus1286
3bpdel
ACAminus1291
9bpdel
CTAG
ACTA
A
174T2
DM
and412healthy
23ndash79MF
Tehran
Case
control
PCR
sequ
encing
PCR-RF
LPNon
significance
Meshk
anietal2007
[75]
PPAR120574
Pro12Ala
412T2
DM
and284healthy
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LPNegatives
ignificantassociatio
nbetweenProAlaor
AlaA
lacarriersandT2
DM
(P=0003)
Journal of Diabetes Research 9
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
T2DM
patie
ntsa
ndinsulin
resistance
Nam
varanetal2012
[76]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin
receptor-2+795G
A
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTG
carriersandT2
DM
(P=0032)
(ii)N
onsig
nificantassociatio
nbetween+7
94GA
carriersand
insulin
resistance
Nam
varanetal2011[77]
PPAR120574
Pro12Ala
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
Realtim
ePCR
Positives
ignificantassociatio
nbetweenAlaallelecarriersand
T2DM
(P=0036)
Hossein-nezhadetal2009
[78]
VDRFokI
(FFFfff
)105T2
DM55plusmn10yrM
FTehran
Case
serie
sPC
R-RF
LPPo
sitives
ignificantassociatio
nbetweenffcarriersandinsulin
resistanceind
ex(P
=002)
Moo
sapo
oretal2007
[79]
PTPN
1148insG
71T2
DM
and264ND
20ndash80y
rMF
Tehran
Case
control
PCR-RF
LP
Negatives
ignificantassociatio
nbetween148insGcarriersand
insulin
resistanceind
ex(119875=0041)
T2DM
patie
ntsa
ndheartd
iseases
Bayatm
akoo
etal2013
[80]
Paraoxon
ase116
3TA
(L55M)
105CA
DD
Mand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPNon
significance
Bayatm
akoo
etal2012
[81]
Paraoxon
ase1575Ggt
A(Q
192R
)105DMCADand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenRR
carriersand
CADD
M(Plt005)
Estegh
amatietal2012
[82]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin+276G
T114
CADD
Mand127DM
42ndash71yrMF
Tehran
Case
control
PCR-RF
LP
(i)Negatives
ignificant
associationbetween45TT
carriersandCA
D(P
=0033)
(ii)P
ositive
significant
associationbetween276G
GcarriersandCA
D(P
=0023)
Rahimietal2012
[83]
eNOSG8
94T
CETP
B1
102CA
DD
M105
CADN
D101
DMand
92ND45ndash66
yrM
FKe
rmanshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
concom
itant
presence
ofNOS3
TalleleandCE
PTB1
allelewith
T2DM
(P=000
4)andCA
D(119875=0002)
Assalietal2011[84]
AT1RA116
6C145CA
DD
Mand164CA
D
lt50
andge50
yrM
FMashh
adCa
secontrol
PCR-RF
LPPo
sitives
ignificantassociatio
nof
ACandCC
carrierswith
DM
(119875=001)
Emam
gholipou
retal2009
[85]
Resistin
minus420C
G113CA
Dwith
andwith
outD
M
58plusmn9yrM
FTehran
Crosssectio
nal
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDM
(119875=0009)
10 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Fallahetal2010
[86]
MMP-3minus1612
5A6A
305CA
DD
Mand313DM
61plusmn9yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetween6A
6AcarriersandCA
S(P
=0008)
Vaisi-Raygani
etal2010
[87]
BChE
KG1
615A
APO
EE2
E3E4
118DM162
CADN
D172
DMCADand
179healthy
42ndash6
8yrMF
Kerm
anshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GAA
Aand
E4carrierswith
CADandDM
(Plt005)
Positives
ignificantassociatio
nof
BChE
KAp
oE4carrierswith
CADand
DM
(Plt005)
Sign
ificant
associationof
BChE
KAp
oE4with
lipid
profi
le(119875lt005)
Rahimietal2009
[88]
Factor
VLeidenG
1691A
Prothrom
binG2
0210A
MTH
FRC677T
65CA
DD
M52CA
DN
Dand
59healthy46
064y
rMF
Kerm
anshah
Case
control
PCR-RF
LPNon
significance
Nakhjavanietal2007
[89]
ACEID
82DM
with
hypertensio
nand87
DM
with
outh
ypertension
49ndash6
3yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
hypertensio
n(P
=0026)
Vaisi-Raygani
etal2007
[90]
Apolipop
roteinE2E3
E4
152CA
DD
M262
CADN
D
and300healthy35ndash73y
rMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nof
E2andE4
allelec
arrie
rswith
CAD(Plt0001)
T2DM
patie
ntsa
ndneph
ropathy
Rahimietal2013
[91]
eNOS4abG
894T
63T2
DMm
icroalbu
minuria
57T2
DMm
acroalbu
minuria
52T2
DMnormoalbum
inuria
121D
Nand
101h
ealth
y45ndash6
6yrMF
Kerm
anshah
Case
control
PCR
PCR-RF
LP
Positives
ignificantassociatio
nof
4aor
894T
allelecarriersand
macro-(P=001)o
rmicroalbu
minuria(P
=002)
Rahimietal2013
[92]
AT2R
minus1332GA
28T2
DMm
icroalbu
minuria
22T2
DMm
acroalbu
minuria
20T2
DMnormoalbum
inuria
and112healthy43ndash6
3yrMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(P
=0016)
Shahsavare
tal2013
[93]
SUMO4163A
G(M
55V)
50T2
DD
Nand50
T2DM
non-DN25ndash45
yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(Plt005)
Arababadi
etal2012
[94]
IL-10minus592C
A100T2
DMnon
-DN100
T2DMD
Nand100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDN
(119875=0001)
Journal of Diabetes Research 11
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2012
[95]
VEG
F+4
05G
C255T2
DMm
icroalbu
minuria
and235T2
DMnon
albu
minuric
50ndash6
7yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersand
albu
minuria(P
=0002)
Rahimietal2012
[96]
MTH
FRA1298C
C677T
ACEID
72T2
DMM
icAlb
68T2
DMM
acAlband72
T2DMnon
-DN46ndash
65yrM
FKe
rmanshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nof
ACED677T(P
=0035)
and
ACED12
98C(P
=0012)
carrierswith
macroalbu
minuria
Rahimietal2012
[97]
eNOSG8
94T
ACEID
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nbetweenAC
EDcarriersand
macroalbu
minuria(P
=0035)
Feleh
garietal2011[98]
ACEID
68T2
DMm
acroalbu
minuria
and72
T2Dmnormoalbum
inuria
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR
Non
significance
Jafarietal2011[99]
eNOSG8
94T
MTH
FRC677TA
1298C
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
eNOST1298
CandeN
OS
T677Tcarrierswith
macroalbu
minuria(Plt005)
(ii)S
ignificantassociatio
nof
eNOSGT+
TTcarrierswith
lipid
profi
le(Plt005)
Rahimietal2011[100]
ACEID
Factor
VLeidenG
1691A
217mean55both
Kerm
anshah
Case
control
PCR
PCR-RF
LPNon
significance
Arababadi2010[101]
IL-4minus590C
T100T2
DMD
Nand150healthy
33ndash4
7yrMF
Rafsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenCT
carriersandDN
(119875lt0001)
Nosratabadi
etal2010
[102]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DMnon
-DN100
T2DMD
Nand
100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandDN
(119875=0012)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandDN
Rahimietal2010
[103]
MTH
FRC677TA
1298C
72T2
DMm
icrolbum
iunira
68T2
DMm
acroalbu
minuria
and72
T2DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
677T1298C
and677T
1298C
carrierswith
macroalbu
minoria
(Plt0001)
(ii)P
ositive
significant
associationof
CT+T
Tand
677T
1298Ccarrierswith
microalbu
minuria(Plt0001)
12 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2009
[104]
ACEID
129T
2DMm
icrolbum
iunira
48T2
DMm
acroalbu
minuria
and145T
2DMnormoalbum
inuria
594plusmn85y
rMF
Tehran
Crosssectio
nal
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
progressionof
albu
minuria
(119875lt001)b
utno
tits
developm
ent
Nikzamiretal2006
[105]
ACEID
85T2
DMD
N85T2
DMnon
-DN
and91
healthy37ndash6
7yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(119875=0006)b
utno
tDN
T2DM
patie
ntsa
ndretin
opathy
Abbasietal2013
[106]
GST
M1n
ullp
ositive
80DRand80
healthy
30ndash70y
rMF
Rasht
Case
control
ARM
S-PC
RNullgenotypes
ignificant
association
Plt005
Dadbinp
oure
tal2013
[107]
(i)GST
M1n
ullp
ositive
(ii)G
STT1nullp
ositive
57DRand58
non-DR
35ndash6
5yrMF
Yazd
Case
control
Multip
lexPC
R
(i)Nullgenotypeo
fGST
M1o
rGST
T1sig
nificantassociatio
n(119875=004)
(ii)N
onsig
nificantassociatio
nof
GST
T1nu
llcarrierswith
DR
Fegh
hietal2011[108]
VEG
F+4
05G
C119
diabeticsw
ithPD
Rand279
diabeticsw
ithNPD
R47ndash6
6yrMF
Ahvaz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersanddiabetic
retin
opathy
(P=0005)
T2DM
patie
ntsa
ndfoot
ulcer
Amolietal2011[109]
(i)VEG
Fminus7C
T(ii)V
EGFminus2578CA
247T2
DM
with
DFU
241
T2DM
with
outD
FUand
98healthy
43ndash6
4MF
Tehran
Case
control
ARM
S-PC
R
(i)Non
significantassociatio
nof
minus7C
Tcarrierswith
DFU
(ii)P
ositive
significant
associationbetweenAAcarriers
andDFU
(P=003)
SNPsin
glenu
cleotid
epo
lymorph
ismT
1DMtype1d
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4T2
DMtype2diabetes
mellitusP
CRp
olym
erasechainreactio
nRF
LPrestrictio
nfragmentlengthpo
lymorph
ismILinterle
ukinSS-PC
Rsequ
ence
specificP
CRV
DR
vitamin
DreceptorT
AP2
transpo
rter
2AT
P-bind
ingcassetteA
RMS-PC
Ram
plificatio
nrefractory
mutationsyste
mPC
RPC
R-SSPPC
Rsin
glespecificprim
erT
GF120573
transform
inggrow
thfactor120573D
Md
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4
MODY
maturity
onsetd
iabeteso
fthe
youn
gHNF-
1120572h
epatocytenu
clear
factor
1120572M
VCm
icrovascular
complicationsT
CF7L
2transcrip
tionfactor
7-lik
e2PC
R-SSCA
PCR
singlestr
andconformationpo
lymorph
ismanalysis
ER120572estr
ogen
receptor120572N
D
nond
iabeticsTC
totalcholesterolTG
trig
lycerid
esP
PAR-1205742peroxisomep
roliferator-activates
receptor120574G
LP-1R
glucagon
-like
peptid
1receptorAPO
apo
lipop
roteinC
XCL5chemokineC
-X-C
motifligand
5SD
F-1120573stro
malderiv
edfactor-1120573IRS
1amp2insulin
receptor
substrate1amp
2GSTglutathione-S-tr
ansfe
raseSLC
30A8solublecarrier3
0A8KC
NJPo
tassium
inwardly-rectify
ingchanneleN
OSendo
thelial
nitricoxidesynthaseVNTR
variablen
umbero
ftandem
repeatsEN
PP1ectoenzymen
ucleotidep
yrop
hosphateph
osph
odieste
rase1SU
MOsmallubiqu
itin-lik
emod
ifier4UCP
2un
coup
lingp
rotein
2MTH
FR
methylenetetrahydrofolateredu
ctaseIFN120574interferon120574C
CR5C-
Cchem
okiner
eceptortype5
INSR
insulin
receptorC
SGE
conformation-sensitive
gelelectroph
oresis
ACE
angiotensin
Icon
vertingenzyme
HFE
hem
ochrom
atosisgenePTP
N1proteintyrosin
Phosph
atase1B
CADcoron
arya
rteryd
iseaseCE
TPcho
leste
ryleste
rtransferp
roteinA
T1R
angiotensin
IreceptorMMP3
matrix
metalloproteinase
3CA
Scoronary
artery
steno
sisB
ChEK
Butyrylcho
linesteraseK
DNdiabetic
neph
ropathyAT
2Rang
iotensin
IIreceptorV
EGFvascularepith
elium
grow
thfactorD
Rdiabeticretin
opathy
PDR
proliferativ
ediabetic
retin
opathy
NPD
Rno
n-PD
RDFU
diabetic
foot
ulcer
Journal of Diabetes Research 13
321 T1DM Related Genes All the studies in this subgroupincluding 12 studies [22ndash33] were in a case control studydesign using PCR (polymerase chain reaction) [33] PCR-RFLP (restriction fragment length polymorphism) [22 2325 26 32] PCR-SSP (single specific primer) [24 28ndash32]and ARMS-PCR (amplification refractory mutation systemPCR) [27] method In all studies both men and women wereincluded and the overall 2519 subjects were under 40 yearsold
Association of interleukins including IL-18 (interleukin)and IL-12 with T1DM revealed that the minus137CG polymor-phism of IL-18 had significant association with T1DM (119875 =0037 119875 = 00001) while no significant relation was observedbetween minus607AC variant of this gene and T1DM [24 28]Investigating IL-12 also showed that there was a significantassociation between +1188AC polymorphism of this geneand T1DM (119875 = 0035) [30]
In 2 studies the association of +49AG variant of CTLA-4 (cytotoxic T lymphocyte associated antigen 4) was investi-gated and it was revealed that there was a positive significantassociation between AG genotype and T1DM (119875 = 001 119875 lt0001) [22 32] One of these studies also revealed that therewas a negative relation betweenAA genotype and T1DM [32]
Vitamin D receptor (VDR) was investigated in 2 studies[25 26] Both of them assessed the association of FokI BsmIApaI and TaqI variants of VDR with T1DM In one studywhichwas performed on 114 subjects Aa (119875 = 0003) FF (119875 =0008) and Bb (119875 = 0014) genotypes were shown to be pos-itively associated with T1DM but no significant associationwas observed between TaqI polymorphism and T1DM [25]Another study which was performed on 187 subjects showedno significant association between T1DM and FokI BsmIand ApaI However TT genotype was observed to be morefrequent in controls (119875 = 0007) and negatively associatedwith T1DM [26]
Different polymorphisms of TAP2 and their associationwith T1DM were investigated in 191 subjects It was shownthat Ile379Val and Stop687Gln had significant associationwith T1DM (119875 = 0001 and 119875 = 0013 resp) Other variantsof TAP2 (transporter 2 ATP-binding cassette) includingAla565Thr Arg651Cys and Ala665Thr were not associatedwith T1DM significantly [27]
Association of alleles A2ndashA9 of CD4 with T1DM wasassessed in 200 subjects It was revealed that A3 allele hadnegative (119875 = 0025) and A5 had positive (119875 = 0001)significant association with T1DM [33]
Association of some other genes including osteopontin(rs1126772 polymorphism) integrin 1205724 (rs1449263 polymor-phism) CD44 (rs8193 polymorphism) and TGF120573 (trans-forming growth factor) (+915CG polymorphism) was alsoinvestigated in 2 studies and no significant relation wasobserved between these variants and T1DM [23 29]
322 MODY In this category only one study was found [34]and the association of Val255Met polymorphism of HNF120572and diabetes was investigated in 101 subjects includingMODY subjects their relatives and healthy controls [34]Thestudy was designed as a case control association study andPCR-RFLP and direct sequencing was used for genotyping
of variants Val255Met mutation in this investigation wasobserved in MODY subjects and their relatives but not incontrol group
323 T2DM Related Genes In this subgroup 42 studieswere assessed and all of them were designed as case controlassociation studies [22 35ndash68 70ndash75] except for one whichwas cross sectionally designed [69] In 33 studies PCR- RFLPwas used for genotyping [22 36ndash38 40ndash54 56 58ndash61 63ndash66 69 72ndash75] In 5 of them PCR was used [35 57 62 70 71]and the remaining studies PCR-SCA [39] real-timePCR [55]ARMS-PCR [66] Gap PCR [67] and CSGE (conformation-sensitive gel electrophoresis) sequencing [68] as the genotyp-ing method were applied
Association between two polymorphisms of TCF7L2including rs7903146 (CT) and rs12255372 (GT)was assessedin three studies [38 48 53] In one study investigatingrs7903146 (CT) in 466 subjects significant difference in thefrequency of CC and CT genotypes was observed betweenT2DM and control group (119875 = 0045) [38] However inanother study this polymorphism showed a positive signifi-cant associationwith TT genotype in T2DM (119875 = 0008) [53]Investigation of rs12255372 (GT) polymorphism of TCF7L2in another study showed that among 491 subjects there wasa positive significant association between TT carriers andT2DM (119875 = 0014) [48]
Investigating the association of calreticulinwith T2DM in650 subjects showed two mutations only in case group 9 bpdeletion of 397ndash399 codons and GgtT mutation at IVSII-142[39]
Association of estrogen receptor 120572 and its PvuII(PPPppp) and XbaI(XXXxxx) polymorphism with T2DM intwo studies was assessed [40 49] In one study the significantassociation of PvuII and XbaI polymorphisms with T2DMwas observed (119875 = 0014 and 119875 = 0002 resp) [40] Inanother study it was revealed that pooled Pp+pp and XX+xxmale carriers have positive significant associationwithT2DM(119875 = 0001 and 119875 = 0026 resp) [49]
Association of Pro12Ala polymorphism of PPAR120574 withT2DMwas investigated in three studies [41 69 75] Negativesignificant association of AlaAla genotype with T2DM wasobserved in two studies (119875 = 0003) [41 75] AlaPro carrierswere shown to be positively associated in one study [41] andnegatively associated in another study [75] with T2DM (119875 lt0001 and 119875 = 0003 resp) However in the third studyno significant association was observed between Pro12Alapolymorphism of PPAR120574 and T2DM [69]
Association of different polymorphisms of ApoAI withT2DM was investigated in two studies [43 72] In one studyinvestigation of MSPI polymorphism showed no significantassociation with T2DM [43] In another study it was shownthat G-75A polymorphism of ApoAI was not associated withT2DM while a significant association was found betweenC+83T polymorphism and T2DM (119875 = 0028) [72]
Two studies assessed the association of minus156GgtC poly-morphism of CXCL5 with T2DM [44 65] In one studypositive significant association of GC carriers (119875 = 0006)and negative association of GG carriers (119875 = 001) was foundbetween diabetic patients and healthy controls [44] and
14 Journal of Diabetes Research
in another study positive significant association was foundbetween GC or CC carriers and T2DM (119875 = 0009) [64]
Adiponectin and its association with T2DM were inves-tigated in two studies [56 73] In one study two variantsincluding +45TG and minus11391GA were investigated but nosignificant relation was found between these two polymor-phisms and T2DM [56] However in another study investi-gating +45TG polymorphism of adiponectin it was revealedthat nonobese T2DM subjects had significantly higher TTgenotype (119875 = 004) [73]
In one study that investigated insulin receptor gene thefollowing mutations were found only in T2DM 511CgtA514TgtG 586 and 628TgtA on exon 2 694GgtC 680GgtA onexon 3 1627AgtT on exon 8 ATgtTG on intron 9 2007CgtCTon exon 9 2595CgtCT and 2669GgtCG on exon 13 2706 and2717CgtG 2752CgtT and 2753CgtG on exon 14 and 3471TgtAand 3516TgtG on exon 19 These mutations were not seen incontrol subjects [68]
Other variants which had significant association withT2DM included haptoglobin (allele 2-2) leptin (G-2548Apolymorphism) paraoxonase 2 (Ser311Cys polymorphism)GST (glutathione-S-transferase) M1 and GSTM1GSTT1interaction calpain-10 (SNP (single nucleotide polymor-phism) 43) IRS-1 (G972R polymorphism) and IRS-2(G1057D polymorphism) VDR (vitamin D receptor) (TaqIpolymorphism) KCNJ11 (E23K polymorphism) eNOS(endothelial nitric oxide synthase) VNTR (intron 4 ab pol-ymorphism) resistin (minus420CG polymorphism) and ACE(InsertionDeletion) [35ndash37 45 47 50 55 57 58 64 70]
In contrast to above variants CTLA4 (+49AG poly-morphism) HNF-1120572 (Ala98Val polymorphism) GLP-1R(glucagon-like peptid 1 receptor) (Thr149Met polymor-ohism) SLC30A8 (Arg325Trp polymorphism) GSTP1(Ile105Val polymorphism) glucokinase (minus30GA polymor-phism) SDF-1120573 (stromal derived factor -1 120573) (G801A poly-morphism) ApoE (apolipoprotein E) ENPP1 (ectoenzymenucleotide pyrophosphate phosphodiesterase 1) (K121Q poly-morphism) SUMO4 (small ubiquitin-like modifier 4)Met55Val polymorphism) MTHFR (C677T polymorphism)UCP2 (uncoupling protein 2) (minus866GA polymorphism)5HTTLPR IL-4 (minus590CT polymorphism) IFN-120574 (inter-feron 120574) (+874TA polymorphism) CCR5 (C-C chemokinereceptor type 5) (12057532mutation) HFE (hemochromatosisgene) (H63D C282Y PTPN1 (protein tyrosin Phosphatase1B)minus51delA minus451AgtG minus467TgtC minus1023CgtA minus1045GgtAminus1286 3 bp del ACA minus1291 9 bp del CTAGACTAA poly-morphisms) were not significantly associated with T2DM[22 42 46 50ndash52 54 59ndash63 66 67 71 74]
324 Genes Related to Insulin Resistance In this subgroupfour studies were assessed and all were designed as case-control association studies Three studies used PCR-RFL [7678 79] and one study used real-time PCR [77] for genotyping
The studies assessed in this subgroup showed a positiveassociation of TG carriers of +45TG polymorphism ofadiponectin (119875 = 0032) and Ala allele carriers of Pro12Alapolymorphism of PPAR120574 (119875 = 0036) with T2DM [76 77]A positive significant association of ff carriers of VDR wasalso shown (FokI polymorphism) (119875 = 002) and negative
association of 148insG carriers of PTPN1 (148insG polymor-phism) (119875 = 0041) with insulin resistance index [7879] However no significant association was shown betweenadiponectin receptor-2+795GA and T2DM [76]
325 Genes Related to Cardiovascular Disease in DiabetesDesign of all 11 studies in this subgroup was case-controlassociation study [80ndash84 86ndash90] except one study which wasdesigned as cross sectional [85] PCR-RFLP was used in all ofthem for genotyping [80ndash88 90] except in one study whichused ARMS-PCR method [89]
Paraoxonase 1 (163TA polymorphism) was the only vari-ant in this subgroup which was not significantly associatedwith atherosclerosis risk in T2DM [80] Investigation ofanother polymorphism of Paraoxonase 1 (Q192R) revealedthat diabetics with CAD had significant increase in RRgenotype (119875 lt 005) [81]
Investigating B1 and B2 alleles of CETP TaqI B allele in400 subjects showed that pooling of B1B1+B1B2 and B1B1genotypes had significant association with T2DM and CAD(119875 lt 001) On the other hand assessing the G894T poly-morphism of eNOS showed positive significant associationbetween TG and TT carriers and CAD (119875 lt 005) It was alsoshown that concomitant presence of NOS3 T allele and CEPTB1 allele was significantly associated with T2DM (119875 = 0004)and CAD (119875 = 0002) [83]
Investigation of apolipoprotein E (E2 E3 and E4) allelesshowed the association of E2 and E4 alleles with CAD(119875 lt 0001) [84 87] Also it was shown that interactionof butyrylcholinesterase (BChE K) and apolipoprotein E(ApoE) was associated significantly with CAD and diabetesApoE4BChE K had significant association with lipid profilesas well (119875 lt 005) [87]
Adiponectin +276GT and +45TG were significantlyassociated with CAD (119875 = 0023 and 0033 resp) [82] whileinvestigating minus1612 5A6A polymorphism of MMP-3 (matrixmetalloproteinase 3) showed a significant association withCAS (coronary artery stenosis) (119875 = 0008) [86]
In addition A1166C polymorphism of AT1R (angiotensinI receptor) and minus420CG polymorphism of resistin in dia-betic patients with CAD revealed significant association withdiabetes 119875 = 001 and 119875 = 0009 respectively [84 85]
Another study showed insertion(I)deletion(D) polymor-phismof angiotensin converting enzyme (ACE)DDgenotypewas significantly associated with higher blood pressure (119875 =0026) [89]
Factor V Leiden (G1691A polymorphism) prothrombin(G20210A polymorphism) and MTHFR (methylenetetrahy-drofolate reductase) (C677T polymorphism) were the vari-ants which were not significantly associated with CAD andT2DM in this subgroup [88]
326 Genes Related to Diabetic Nephropathy All of 15 studiesin this subgroup were designed as case-control associationstudies [91ndash106] In 7 studies PCR-RFLP was used forgenotyping [92ndash95 99 102 103] in four studies PCRwas used[98 101 104 105] and in 4 of them both PCR and PCR-RFLPwere used [91 96 97 100]
Journal of Diabetes Research 15
Studying the association of 163AG polymorphism ofSUMO4 showed a positive significant association betweenAA carriers and diabetic nephropathy (119875 lt 005) [93]
Studying the interaction of eNOS4ab and G894Trevealed positive significant association between 4a or 894Tallele carriers and macro- and microalbuminuria (119875 = 001119875 = 002 resp) [91] It was observed that the interaction ofeNOS (G894T polymorphism) andACE (ID alleles) was sig-nificantly associated with more frequent macroalbuminuria(119875 = 0035) [97]
It has also been shown that interaction of eNOS (G894Tpolymorphisms) and MTHFR (C677T and A1298C poly-morphisms) eNOS T1298 C and eNOS T677 T carriershad positive significant association with macroalbuminuriaIn addition significant association of eNOS GT+TT carrierswith lipid profile (119875 lt 005) was shown in this study [99]
C677T andA1298C polymorphisms ofMTHFRwere alsoinvestigated in another study revealing that 677T 1298Cand 677T1298C carriers were significantly associated withmacroalbuminuria (119875 lt 0001) Positive significant asso-ciation when pooling CT+TT genotypes and 677T1298Cwas also found with microalbuminuria (119875 lt 0001) [103]Investigating the interaction of MTHFR (A1298C C677Tpolymorphisms) and ACE (ID alleles) showed a positivesignificant association of ACE D677T (119875 = 0035) and ACED1298C (119875 = 0012) genotypeswithmacroalbuminuria [96]
ACE (ID alleles) polymorphisms were investigated inthree studies In one study positive significant association(119875 lt 001) between DD carriers and progression but notdevelopment of albuminuria was observed [104] In anotherstudy in nephropathic subjects association of DD carriersand T2DM (119875 = 0006) but not nephropathy was revealed[105] However another study did not show significant asso-ciation of ACE with macroalbuminuria [98] Interaction ofACE (ID alleles) with Factor V Leiden (G1691A polymor-phism) was not significant [100]
Association of interleukins including IL-4 and IL-10 withdiabetic nephropathy was also investigated in two studiesStudy of minus592CA polymorphism of IL-10 revealed positivesignificant association between CC carriers and nephropathy(119875 = 0001) [94] and study ofminus590CTpolymorphismof IL-4revealed positive significant association between CT carriersand nephropathy (119875 lt 0001) [101]
Other significant associations between variants and dia-betic nephropathy included AT2R (angiotensin II recep-tor) (minus1332GA polymorphism) VEGF (vascular epitheliumgrowth factor) (+405GC polymorphism) and VDR (TaqIpolymorphism) [92 95 102] ApaI polymorphism of VDRwas not significantly associated with diabetic nephropathy[102]
327 Genes Related to Diabetic Retinopathy All of the 3studies in this subgroup were conducted as case-controlassociation studies [106ndash108]
Investigating nullpositive genotype of GSTM1 in a studywhich used ARMS-PCR for genotyping revealed that nullgenotype is significantly associated with diabetic retinopathy(119875 lt 005) [106] This result was confirmed in another study
by using multiplex PCR as genotyping [107] although nosignificant association between GSTT1 and retinopathy wasfound in this study [107]
Investigating +405GC polymorphism of VEGF alsorevealed positive significant association between GG carriersand diabetic retinopathy (119875 = 0005) [108]
328 Genes Related to Diabetic Foot Ulcer In this subgrouponly one study was found [109] which was case-controldesigned and used ARMS-PCR for genotyping In this studyassociation of minus7CT and minus2578CA polymorphisms ofVEGF with diabetic foot ulcer (DFU) was investigated and apositive significant association betweenAA carriers andDFU(119875 = 003) was observed But no significant association wasfound between minus7CT of VEGF and DFU [109]
4 Discussion
Diabetes mellitus is the eighth most frequent disease leadingcause of death throughout the world and now ranks the fifthfollowing communicable diseases cardiovascular diseasecancer and injuries [110] Prevalence of diabetes mellitus isincreasing worldwide [6]
Type 2 diabetes is the most frequent type of diabetesmellitus [110 111] Multiple genes and environmental factorsaffect the prevalence of T2DM Systematic review and meta-analysis studies have assessed the association between dif-ferent genes and T2DM Glutathione-S-transferase includingGSTMI GSTM1 and GSTP1 are important genes and theirassociation with diabetes has been investigated in two meta-analysis studies [112 113] It was revealed that null genotypeof both GSTM1 and GSTT1 could be as a risk factor fordiabetes while no significant association was found betweenGSTP1 and diabetes [112 113] These results are in linewith our finding and confirming the association of the nullgenotype of GSTT1 and GSTM1 with T2DM in Iranianpopulation [50] The relation between GSTT1 and GSTM1and diabetic retinopathy has also been shown in Iranianpopulation [106 107]
MTHFR is another important gene in association withT2DM and other related complications No associationof C677T polymorphism of MTHFR gene was found inAfricans Asians and Caucasians [114] MTHFR is a genewhich is involved in DNA methylation and synthesis andregulated folate activity It has been reported that mutanthomozygote and heterozygote of C677T polymorphism ofMTHFR increase plasma homocysteine which is an impor-tant factor leading to diabetic nephropathy (DN) and as aresult C677T polymorphism of MTHFR can be associatedwith the development of DN In Caucasians this associationhas also been observed [115] In Iranian population in linewith other populations no significant association was foundbetween MTHFR polymorphisms and T2DM [63] althoughsignificant association of 677T and 1298C alleles with diabeticnephropathy was observed [87] Interaction of two polymor-phisms and also interaction of MTHFR polymorphisms withother genes such as ACE and eNOS showed an associationwith development of DN [96 99]
16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
4 Journal of Diabetes Research
Table1Ch
aracteris
ticso
fincludedarticlesinsyste
maticreview
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
T1DM
andcomplications
Ahm
adietal2013
[22]
CTLA
-4+49AG
60T1DM56T2
DMand
107
healthymale(M)female(F)
Kurdistan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAG
carriersandT1DM
(P=001)
Karamizadeh
etal2013
[23]
(i)Oste
opon
tinrs11
26772
(ii)Integrin1205724rs1449263
CD44
rs8193
87T1DM
and86
healthy
lt20
yrM
FSh
iraz
Case
control
PCR-RF
LPNon
significance
Rahb
ani-N
abar
etal2013
[24]
IL-18minus137C
G104T1DM
and92
healthy
9ndash32
yrM
FTabriz
Case
control
SS-PCR
Positives
ignificantassociatio
nbetweenGGcarriersandT1DM
(P=0037)
Bonakd
aran
etal2012
[25]
(i)VDRFokI
(FFFfff
)(ii)B
smI(BB
Bbbb)
ApaI
(AA
Aaaa)
(iii)TaqI
(TTTttt)
69T1DM
and45
healthy
lt35
yrM
FMashh
adCa
secontrol
PCR-RF
LP
Positives
ignificantassociatio
nbetweenAa(
P=0003)FF
(P=0008)and
Bb(P
=0014)
carrierswith
T1DMsignificant
associationbetweenffgeno
type
andhisto
ryof
ketoacidosis
(P=004)
Moh
ammadnejadetal2012
[26]
(i)VDRTaqI
(TTTttt)
(ii)V
DR
FokIB
smIAp
aI87
T1DM
and100healthy
17ndash38y
rMF
Mashh
adCa
secontrol
PCR-RF
LP
(i)Negatives
ignificant
associationbetweenTT
carriers
andT1DM
(P=0007)
(ii)N
onsig
nificance
association
betweenotherc
arrie
rsof
VDR
andT1DM
Afsharietal2011[27]
(i)TA
P2Ile379Va
l(ii)T
AP2
Stop687Gln
(iii)TA
P2Ala565Th
rArg651Cy
sAla665Th
r
87T1DM
and104healthy
lt30
yrM
FMashh
adCa
secontrol
ARM
S-PC
R
(i)Sign
ificant
association
betweenIle
379V
alandT1DM
(P=0001)
(ii)S
ignificantassociatio
nbetweenStop
687G
lnandT1DM
(P=0013)
(iii)Non
significantassociatio
nbetweenotherc
arrie
rsof
TAP2
andT1DM
Massoud
etal2009
[28]
(i)IL-18minus137C
G(ii)IL-18minus607A
C75
T1DM
and88
healthy
lt30
yrM
FTehran
Case
control
PCR-SSP
(i)Po
sitives
ignificantassociatio
nbetweenGGcarriersandT1DM
(P=000
01)
(ii)S
ignificantassociatio
nbetweenCC
geno
type
with
T1DM
(P=000
01)
(iii)Non
significance
association
betweenotherc
arrie
rsof
IL-18
andT1DM
Journal of Diabetes Research 5
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Masou
detal2007
[29]
TGF120573
+915C
G75
T1DM
and88
healthy
lt30
yrM
FTehran
Case
control
PCR-SSP
Non
significance
Masou
detal2007
[30]
IL-12+1188A
C75
T1DM
and88
healthy
lt30
yrM
FTehran
Case
control
PCR-SSP
Sign
ificant
associationbetween
AAandAC
geno
type
andT1DM
(P=0035)
Mojtahedi
etal2006
[31]
IL-18minus607A
C
minus137C
G112T1DM
and194no
n-DM
lt15
andgt15yrM
FSh
iraz
Case
control
PCR-SSP
minus137C
Candminus607A
Aminus137C
Csig
nificantassociatio
nwith
T1DM
inon
setgt
15yr
(P=0027)
Mojtahedi
etal2005
[32]
CTLA
-4+49AG
109T1DM
and331h
ealth
y0ndash
37yrM
FSh
iraz
Case
control
PCR-SSP
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenAG
carriersandT1DM
(P=000)
(ii)N
egatives
ignificant
associationbetweenAAcarriers
andT1DM
(P=000)
Zamanietal2005
[33]
CD4A2
ndashA9
92T1DM
and108healthy
gt35
yrM
FTehran
Case
control
PCR
Negatives
ignificantassociatio
nbetweenA3alleleandT1DM
(P=0025)
Positives
ignificantassociatio
nbetweenA5alleleandT1DM
(P=0001)
MODY
Tagh
avietal2009
[34]
HNF120572
Val255M
et30
MODY21
relativ
esand
50healthy25ndash35y
rMF
Mashh
adCa
secontrol
PCR-FL
Psequ
encing
Them
utationwas
foun
din
patie
ntsa
ndrelatives
butn
otin
controls
T2DM
andcomplications
Ahm
adietal2013
[22]
CTLA
-4+49AG
Said
above
Said
above
Said
above
Said
above
Non
significance
Amiri
etal2013
[35]
Haptoglob
in1-
12-12-2
134T2
DM
with
MVC
s71
T2DM
with
outM
VCs
46ndash72y
rMF
Sari
Case
control
PCR
Hp2-2
high
lysig
nificantfor
T2DM
(P=005)
And
alib
etal2013
[36]
Paraoxon
ase2
Ser311Cys
100T2
DM
and100healthy
51yrM
FIsfahan
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
CysCy
sand
CysSerc
arrie
rsand
negativ
esignificantassociatio
nof
SerSerc
arrie
rswith
T2DM
(Plt005)
Kohanetal2013
[37]
LeptinG
-2548A
100T2
DM
and100healthy
44ndash6
6yrMF
Arsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersandT2
DM
(P=000
4)
Alamietal2013
[38]
TCF7L2
rs7903146
(CT)
233T
2DM
and233controls
gt40
yrM
FGorgan
Case
control
PCR-RF
LPCC
andCT
geno
typessignificant
differenceb
etweenT2
DM
and
controls(P
=0045)
Mahmazietal2013
[39]
Calre
ticulin
120T2
DM
and530controls
43ndash6
6yrMF
Zanjan
Case
control
PCR-SC
A9b
pdeletio
nof
397ndash399codo
nsGgtTmutationatIV
SII-142in
T2DM
notincontrols
6 Journal of Diabetes ResearchTa
ble1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Moh
ammadietal2013
[40]
(i)ER120572PvuII(PPPp
pp)
(ii)E
R120572XbaI(XX
Xxxx)
174T2
DM
and174ND
35ndash6
5yrMF
Jahrom
Case
control
PCR-RF
LP
(i)Sign
ificant
associationwith
T2DM
(P=0014)
TC(P
=0007)and
TG(119875=0005)fem
alec
arrie
rs(ii)S
ignificantassociatio
nwith
T2DM
(119875=0002)TC
(119875=0003)andTG
(119875=0009)
femalec
arrie
rs
Motavallianetal2013
[41]
PPAR-1205742Pro12A
la100T2
DM
and100healthy
51yrM
FIsfahan
Case
control
PCR-RF
LP
Negatives
ignificantassociatio
nbetweenAlaA
lacarriers
(119875lt0001)a
ndpo
sitive
significantassociatio
nbetween
AlaPro
carrierswith
T2DM
(119875lt0001)
Sepahi
etal2013
[42]
HNF-1120572Ala98Va
lGLP
-1RTh
r149Met
100T2
DM
and50
healthy
controlsle35
andgt35
yrM
FMashh
adCa
secontrol
PCR-RF
LPNon
significance
Sheikh
haetal2013
[43]
APO
A1M
SP-I
200T2
DM
and200healthy
418yrM
FYazd
Case
control
PCR-RF
LPNon
significance
Yagh
oubietal2013
[44]
CXCL
5minus156GgtC
100T2
DM54y
rand
100healthy
56yrM
FArdabil
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GCcarriers(119875=0006)a
ndnegativ
esignificantassociatio
nof
GGcarrierswith
T2DM
(P=001)
Bahreini
etal2012
[45]
Calpain-10SNP4
3(AG)
102T2
DM
and100healthy
40ndash70y
rM
EastAzerbayjan
Case
control
PCR-RF
LPGallelea
srisk
factor
ofT2
DM
(P=0037)
Derakhshanetal2012
[46]
SDF-1120573G
801A
200T2
DM
and200healthy
40yrM
FRa
fsanjan
Case
control
PCR-RF
LPNon
significance
Haghani
etal2012
[47]
(i)IRS-1G
972R
(ii)IRS
-2G
1057D
336T2
DM
and341h
ealth
y44
ndash63y
rMF
Ilam
andKe
rmanshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
GR(P
=0001)andRR
(119875=00001)carrie
rswith
T2DM
(ii)P
ositive
significant
associationbetweenGDcarriers
andT2
DM
(P=0016)
Alamietal2012
[48]
TCF7L2
rs12
255372
(GT)
236T2
DM
and255healthy
gt37
yrM
FGorgan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersandT2
DM
(P=0014)
Meshk
anietal2012
[49]
(i)ER120572PvuII(PPPp
pp)
(ii)E
R120572XbaI(XX
Xxxx)
155T2
DM
and377controls
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
pooled
Pp+pp
malec
arrie
rs(P
=0001)with
T2DM
(ii)P
ositive
significant
associationof
pooled
XX+
xxmalec
arrie
rs(P
=0026)
with
T2DM
Journal of Diabetes Research 7
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Moasser
etal2012
[50]
GST
M1p
resentnull
GST
T1presentnull
GST
P1Ile105Va
l
171T
2DM
and169healthy
25ndash6
5yrMF
Shira
zCa
secontrol
PCR-RF
LP
GST
M1-n
ull(P=0016)
and
interactionof
GST
M-nullG
STT1-null
(119875=0022)significant
associationwith
T2DM
Moh
addese
tal2012
[51]
SLC3
0A8Arg325Trp
125T2
DM
and125controls
40ndash70y
rMF
Azarbayjan
Case
control
PCR-RF
LPNon
significance
Oladi
etal2012
[52]
Glucokinaseminus30GA
542subjects
18ndash6
5yrMF
Mashh
adCr
osssectio
nal
PCR-RF
LPNon
significance
Palizbanetal2012
[53]
TCF7L2
rs7903146
(CT)
110T2
DM
and80
healthy
46ndash6
7yrMF
Isfahan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersandT2
DM
(P=0008)
Tabatabaei-M
alazyetal2012
[54]
ApoE
E3-E3
E2-E3
E4-E3
156T2
DM
and155healthy
25ndash6
5MF
Tehran
Case
control
PCR-RF
LPNon
significance
Ghasemietal2012
[55]
KCNJ11
E23K
358T2
DM
and388healthy
41ndash6
9yrMF
Rasht
Case
control
Realtim
ePCR
Positives
ignificantassociatio
nbetweenKK
carriersandob
ese
T2DM
(P=0037)
Ranjbare
tal2011[56]
Adipon
ectin
+45TG
minus113
91GA
244T2
DM
and99
healthy
37ndash6
5yrMF
Rafsanjan
Case
control
PCR-RF
LPNon
significant
Mehrab-Moh
seni
etal2011[57]
eNOSVNTR
intro
n4ab
220T2
DM
and96
healthy
53plusmn15yrM
FRa
fsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenaa
orab
carriersand
T2DM
(P=002)
Nosratabadi
etal2011[58]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DM
and100healthy
40yrM
FRa
fsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandT2
DM
(Plt0001)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandT2
DM
Saberietal2011[59]
ENPP
1K121Q
155T2
DM
and377healthy
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LPNon
significance
Fallahetal2010
[60]
SUMO4Met55Va
l(16
3AG
)50
T2DM
and50
healthy
25ndash4
5yrMF
Tehran
Case
control
PCR-RF
LPNon
significance
Heidarietal2010
[61]
UCP
2minus866G
A75
T2DM75NDob
esea
nd75
NDno
nobese35ndash76
yrM
FTehran
Case
control
PCR-RF
LPNon
significance
Nazem
etal2010
[62]
5HTT
LPRSSSLLL
90T2
DM
and90
healthy
54ndash6
6yrMF
Shira
zCa
secontrol
PCR
Non
significance
Bazzaz
etal2010
[63]
MTH
FRC677T
401T
2DM74NDob
esea
nd207
NDno
nobese30ndash
63yrM
FTehran
Case
control
PCR-RF
LPNon
significance
Emam
gholipou
retal2009
[64]
resistin
minus420C
G47
T2DM
and66
healthy
58plusmn9y
rMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandT2
DM
(P=000
9)
Hasani-R
anjbar
etal2009
[65]
CXCL
5minus156G
C230T2
DM
and120healthy
40ndash6
3yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGCor
CCcarriersand
T2DM
(P=000
4)
8 Journal of Diabetes ResearchTa
ble1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
KazemiA
rababadi
etal2009
[66]
IL-4minus590C
TIFN-120574+874T
A160T2
DM
and160healthy
38plusmn9y
rMF
Rafsanjan
Case
control
PCR-RF
LPARM
S-PC
RNon
significance
Arababadi
etal2009
[67]
CCR5
12057532mutation
200T2
DM
and300healthy
40plusmn9y
rMF
Rafsanjan
Case
control
Gap-PCR
Non
significance
Kazemietal2009
[68]
INSR
128T2
DMgt
40yrM
FTehran
Case
control
PCR
CSGE
sequ
encing
Follo
wingmutations
werefou
ndon
lyin
T2DM
511CgtA514Tgt
G586and
628TgtAon
exon
2694GgtCand680GgtAon
exon
31627AgtTon
exon
8ATgtTG
onintro
n9
2007Cgt
CTon
exon
92595Cgt
CTand2669GgtCGon
exon
132706
and2717Cgt
G2752CgtT
2753Cgt
Gonexon
143471Tgt
Aand3516Tgt
Gon
exon
19
Mirz
aeietal2009
[69]
PPAR120574
2Pro12A
la78
norm
al78ob
ese78
T2DM
and78
obeseT
2DM25ndash64
yr
MF
Tehran
Crosssectio
nal
PCR-RF
LPNon
significance
Nikzamiretal2008
[70]
ACEinsertion(I)
deletion(D
)170T2
DM
and144healthyMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(P=002)
Sharifi
etal2008
[71]
HFE
H63D
C282Y
101T
2DM
and101h
ealth
y55plusmn11yrM
FZa
njan
Case
control
PCR
Non
significance
Besharatietal2007
[72]
(i)Ap
oA-IG
-75A
(ii)A
poA-
IC+8
3T215subjects26ndash
64yrM
FTehran
Crosssectio
nal
PCR-RF
LP
(i)Non
significantassociatio
nbetweenG-75A
carriersand
T2DM
(ii)P
ositive
significant
associationbetweenCT
carriers
andT2
DM
(P=0028)
Hasani-R
anjbar
etal2007
[73]
Adipon
ectin
+45TG
80T2
DM
obese72
T2DM
nono
beseand
70healthy
25ndash6
4yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersand
nono
bese
T2DM
(P=004)
Meshk
anietal2007
[74]
PTPN
1minus51delA
minus451AgtGminus467TgtC
minus1023Cgt
Aminus1045GgtAminus1286
3bpdel
ACAminus1291
9bpdel
CTAG
ACTA
A
174T2
DM
and412healthy
23ndash79MF
Tehran
Case
control
PCR
sequ
encing
PCR-RF
LPNon
significance
Meshk
anietal2007
[75]
PPAR120574
Pro12Ala
412T2
DM
and284healthy
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LPNegatives
ignificantassociatio
nbetweenProAlaor
AlaA
lacarriersandT2
DM
(P=0003)
Journal of Diabetes Research 9
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
T2DM
patie
ntsa
ndinsulin
resistance
Nam
varanetal2012
[76]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin
receptor-2+795G
A
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTG
carriersandT2
DM
(P=0032)
(ii)N
onsig
nificantassociatio
nbetween+7
94GA
carriersand
insulin
resistance
Nam
varanetal2011[77]
PPAR120574
Pro12Ala
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
Realtim
ePCR
Positives
ignificantassociatio
nbetweenAlaallelecarriersand
T2DM
(P=0036)
Hossein-nezhadetal2009
[78]
VDRFokI
(FFFfff
)105T2
DM55plusmn10yrM
FTehran
Case
serie
sPC
R-RF
LPPo
sitives
ignificantassociatio
nbetweenffcarriersandinsulin
resistanceind
ex(P
=002)
Moo
sapo
oretal2007
[79]
PTPN
1148insG
71T2
DM
and264ND
20ndash80y
rMF
Tehran
Case
control
PCR-RF
LP
Negatives
ignificantassociatio
nbetween148insGcarriersand
insulin
resistanceind
ex(119875=0041)
T2DM
patie
ntsa
ndheartd
iseases
Bayatm
akoo
etal2013
[80]
Paraoxon
ase116
3TA
(L55M)
105CA
DD
Mand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPNon
significance
Bayatm
akoo
etal2012
[81]
Paraoxon
ase1575Ggt
A(Q
192R
)105DMCADand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenRR
carriersand
CADD
M(Plt005)
Estegh
amatietal2012
[82]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin+276G
T114
CADD
Mand127DM
42ndash71yrMF
Tehran
Case
control
PCR-RF
LP
(i)Negatives
ignificant
associationbetween45TT
carriersandCA
D(P
=0033)
(ii)P
ositive
significant
associationbetween276G
GcarriersandCA
D(P
=0023)
Rahimietal2012
[83]
eNOSG8
94T
CETP
B1
102CA
DD
M105
CADN
D101
DMand
92ND45ndash66
yrM
FKe
rmanshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
concom
itant
presence
ofNOS3
TalleleandCE
PTB1
allelewith
T2DM
(P=000
4)andCA
D(119875=0002)
Assalietal2011[84]
AT1RA116
6C145CA
DD
Mand164CA
D
lt50
andge50
yrM
FMashh
adCa
secontrol
PCR-RF
LPPo
sitives
ignificantassociatio
nof
ACandCC
carrierswith
DM
(119875=001)
Emam
gholipou
retal2009
[85]
Resistin
minus420C
G113CA
Dwith
andwith
outD
M
58plusmn9yrM
FTehran
Crosssectio
nal
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDM
(119875=0009)
10 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Fallahetal2010
[86]
MMP-3minus1612
5A6A
305CA
DD
Mand313DM
61plusmn9yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetween6A
6AcarriersandCA
S(P
=0008)
Vaisi-Raygani
etal2010
[87]
BChE
KG1
615A
APO
EE2
E3E4
118DM162
CADN
D172
DMCADand
179healthy
42ndash6
8yrMF
Kerm
anshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GAA
Aand
E4carrierswith
CADandDM
(Plt005)
Positives
ignificantassociatio
nof
BChE
KAp
oE4carrierswith
CADand
DM
(Plt005)
Sign
ificant
associationof
BChE
KAp
oE4with
lipid
profi
le(119875lt005)
Rahimietal2009
[88]
Factor
VLeidenG
1691A
Prothrom
binG2
0210A
MTH
FRC677T
65CA
DD
M52CA
DN
Dand
59healthy46
064y
rMF
Kerm
anshah
Case
control
PCR-RF
LPNon
significance
Nakhjavanietal2007
[89]
ACEID
82DM
with
hypertensio
nand87
DM
with
outh
ypertension
49ndash6
3yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
hypertensio
n(P
=0026)
Vaisi-Raygani
etal2007
[90]
Apolipop
roteinE2E3
E4
152CA
DD
M262
CADN
D
and300healthy35ndash73y
rMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nof
E2andE4
allelec
arrie
rswith
CAD(Plt0001)
T2DM
patie
ntsa
ndneph
ropathy
Rahimietal2013
[91]
eNOS4abG
894T
63T2
DMm
icroalbu
minuria
57T2
DMm
acroalbu
minuria
52T2
DMnormoalbum
inuria
121D
Nand
101h
ealth
y45ndash6
6yrMF
Kerm
anshah
Case
control
PCR
PCR-RF
LP
Positives
ignificantassociatio
nof
4aor
894T
allelecarriersand
macro-(P=001)o
rmicroalbu
minuria(P
=002)
Rahimietal2013
[92]
AT2R
minus1332GA
28T2
DMm
icroalbu
minuria
22T2
DMm
acroalbu
minuria
20T2
DMnormoalbum
inuria
and112healthy43ndash6
3yrMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(P
=0016)
Shahsavare
tal2013
[93]
SUMO4163A
G(M
55V)
50T2
DD
Nand50
T2DM
non-DN25ndash45
yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(Plt005)
Arababadi
etal2012
[94]
IL-10minus592C
A100T2
DMnon
-DN100
T2DMD
Nand100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDN
(119875=0001)
Journal of Diabetes Research 11
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2012
[95]
VEG
F+4
05G
C255T2
DMm
icroalbu
minuria
and235T2
DMnon
albu
minuric
50ndash6
7yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersand
albu
minuria(P
=0002)
Rahimietal2012
[96]
MTH
FRA1298C
C677T
ACEID
72T2
DMM
icAlb
68T2
DMM
acAlband72
T2DMnon
-DN46ndash
65yrM
FKe
rmanshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nof
ACED677T(P
=0035)
and
ACED12
98C(P
=0012)
carrierswith
macroalbu
minuria
Rahimietal2012
[97]
eNOSG8
94T
ACEID
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nbetweenAC
EDcarriersand
macroalbu
minuria(P
=0035)
Feleh
garietal2011[98]
ACEID
68T2
DMm
acroalbu
minuria
and72
T2Dmnormoalbum
inuria
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR
Non
significance
Jafarietal2011[99]
eNOSG8
94T
MTH
FRC677TA
1298C
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
eNOST1298
CandeN
OS
T677Tcarrierswith
macroalbu
minuria(Plt005)
(ii)S
ignificantassociatio
nof
eNOSGT+
TTcarrierswith
lipid
profi
le(Plt005)
Rahimietal2011[100]
ACEID
Factor
VLeidenG
1691A
217mean55both
Kerm
anshah
Case
control
PCR
PCR-RF
LPNon
significance
Arababadi2010[101]
IL-4minus590C
T100T2
DMD
Nand150healthy
33ndash4
7yrMF
Rafsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenCT
carriersandDN
(119875lt0001)
Nosratabadi
etal2010
[102]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DMnon
-DN100
T2DMD
Nand
100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandDN
(119875=0012)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandDN
Rahimietal2010
[103]
MTH
FRC677TA
1298C
72T2
DMm
icrolbum
iunira
68T2
DMm
acroalbu
minuria
and72
T2DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
677T1298C
and677T
1298C
carrierswith
macroalbu
minoria
(Plt0001)
(ii)P
ositive
significant
associationof
CT+T
Tand
677T
1298Ccarrierswith
microalbu
minuria(Plt0001)
12 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2009
[104]
ACEID
129T
2DMm
icrolbum
iunira
48T2
DMm
acroalbu
minuria
and145T
2DMnormoalbum
inuria
594plusmn85y
rMF
Tehran
Crosssectio
nal
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
progressionof
albu
minuria
(119875lt001)b
utno
tits
developm
ent
Nikzamiretal2006
[105]
ACEID
85T2
DMD
N85T2
DMnon
-DN
and91
healthy37ndash6
7yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(119875=0006)b
utno
tDN
T2DM
patie
ntsa
ndretin
opathy
Abbasietal2013
[106]
GST
M1n
ullp
ositive
80DRand80
healthy
30ndash70y
rMF
Rasht
Case
control
ARM
S-PC
RNullgenotypes
ignificant
association
Plt005
Dadbinp
oure
tal2013
[107]
(i)GST
M1n
ullp
ositive
(ii)G
STT1nullp
ositive
57DRand58
non-DR
35ndash6
5yrMF
Yazd
Case
control
Multip
lexPC
R
(i)Nullgenotypeo
fGST
M1o
rGST
T1sig
nificantassociatio
n(119875=004)
(ii)N
onsig
nificantassociatio
nof
GST
T1nu
llcarrierswith
DR
Fegh
hietal2011[108]
VEG
F+4
05G
C119
diabeticsw
ithPD
Rand279
diabeticsw
ithNPD
R47ndash6
6yrMF
Ahvaz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersanddiabetic
retin
opathy
(P=0005)
T2DM
patie
ntsa
ndfoot
ulcer
Amolietal2011[109]
(i)VEG
Fminus7C
T(ii)V
EGFminus2578CA
247T2
DM
with
DFU
241
T2DM
with
outD
FUand
98healthy
43ndash6
4MF
Tehran
Case
control
ARM
S-PC
R
(i)Non
significantassociatio
nof
minus7C
Tcarrierswith
DFU
(ii)P
ositive
significant
associationbetweenAAcarriers
andDFU
(P=003)
SNPsin
glenu
cleotid
epo
lymorph
ismT
1DMtype1d
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4T2
DMtype2diabetes
mellitusP
CRp
olym
erasechainreactio
nRF
LPrestrictio
nfragmentlengthpo
lymorph
ismILinterle
ukinSS-PC
Rsequ
ence
specificP
CRV
DR
vitamin
DreceptorT
AP2
transpo
rter
2AT
P-bind
ingcassetteA
RMS-PC
Ram
plificatio
nrefractory
mutationsyste
mPC
RPC
R-SSPPC
Rsin
glespecificprim
erT
GF120573
transform
inggrow
thfactor120573D
Md
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4
MODY
maturity
onsetd
iabeteso
fthe
youn
gHNF-
1120572h
epatocytenu
clear
factor
1120572M
VCm
icrovascular
complicationsT
CF7L
2transcrip
tionfactor
7-lik
e2PC
R-SSCA
PCR
singlestr
andconformationpo
lymorph
ismanalysis
ER120572estr
ogen
receptor120572N
D
nond
iabeticsTC
totalcholesterolTG
trig
lycerid
esP
PAR-1205742peroxisomep
roliferator-activates
receptor120574G
LP-1R
glucagon
-like
peptid
1receptorAPO
apo
lipop
roteinC
XCL5chemokineC
-X-C
motifligand
5SD
F-1120573stro
malderiv
edfactor-1120573IRS
1amp2insulin
receptor
substrate1amp
2GSTglutathione-S-tr
ansfe
raseSLC
30A8solublecarrier3
0A8KC
NJPo
tassium
inwardly-rectify
ingchanneleN
OSendo
thelial
nitricoxidesynthaseVNTR
variablen
umbero
ftandem
repeatsEN
PP1ectoenzymen
ucleotidep
yrop
hosphateph
osph
odieste
rase1SU
MOsmallubiqu
itin-lik
emod
ifier4UCP
2un
coup
lingp
rotein
2MTH
FR
methylenetetrahydrofolateredu
ctaseIFN120574interferon120574C
CR5C-
Cchem
okiner
eceptortype5
INSR
insulin
receptorC
SGE
conformation-sensitive
gelelectroph
oresis
ACE
angiotensin
Icon
vertingenzyme
HFE
hem
ochrom
atosisgenePTP
N1proteintyrosin
Phosph
atase1B
CADcoron
arya
rteryd
iseaseCE
TPcho
leste
ryleste
rtransferp
roteinA
T1R
angiotensin
IreceptorMMP3
matrix
metalloproteinase
3CA
Scoronary
artery
steno
sisB
ChEK
Butyrylcho
linesteraseK
DNdiabetic
neph
ropathyAT
2Rang
iotensin
IIreceptorV
EGFvascularepith
elium
grow
thfactorD
Rdiabeticretin
opathy
PDR
proliferativ
ediabetic
retin
opathy
NPD
Rno
n-PD
RDFU
diabetic
foot
ulcer
Journal of Diabetes Research 13
321 T1DM Related Genes All the studies in this subgroupincluding 12 studies [22ndash33] were in a case control studydesign using PCR (polymerase chain reaction) [33] PCR-RFLP (restriction fragment length polymorphism) [22 2325 26 32] PCR-SSP (single specific primer) [24 28ndash32]and ARMS-PCR (amplification refractory mutation systemPCR) [27] method In all studies both men and women wereincluded and the overall 2519 subjects were under 40 yearsold
Association of interleukins including IL-18 (interleukin)and IL-12 with T1DM revealed that the minus137CG polymor-phism of IL-18 had significant association with T1DM (119875 =0037 119875 = 00001) while no significant relation was observedbetween minus607AC variant of this gene and T1DM [24 28]Investigating IL-12 also showed that there was a significantassociation between +1188AC polymorphism of this geneand T1DM (119875 = 0035) [30]
In 2 studies the association of +49AG variant of CTLA-4 (cytotoxic T lymphocyte associated antigen 4) was investi-gated and it was revealed that there was a positive significantassociation between AG genotype and T1DM (119875 = 001 119875 lt0001) [22 32] One of these studies also revealed that therewas a negative relation betweenAA genotype and T1DM [32]
Vitamin D receptor (VDR) was investigated in 2 studies[25 26] Both of them assessed the association of FokI BsmIApaI and TaqI variants of VDR with T1DM In one studywhichwas performed on 114 subjects Aa (119875 = 0003) FF (119875 =0008) and Bb (119875 = 0014) genotypes were shown to be pos-itively associated with T1DM but no significant associationwas observed between TaqI polymorphism and T1DM [25]Another study which was performed on 187 subjects showedno significant association between T1DM and FokI BsmIand ApaI However TT genotype was observed to be morefrequent in controls (119875 = 0007) and negatively associatedwith T1DM [26]
Different polymorphisms of TAP2 and their associationwith T1DM were investigated in 191 subjects It was shownthat Ile379Val and Stop687Gln had significant associationwith T1DM (119875 = 0001 and 119875 = 0013 resp) Other variantsof TAP2 (transporter 2 ATP-binding cassette) includingAla565Thr Arg651Cys and Ala665Thr were not associatedwith T1DM significantly [27]
Association of alleles A2ndashA9 of CD4 with T1DM wasassessed in 200 subjects It was revealed that A3 allele hadnegative (119875 = 0025) and A5 had positive (119875 = 0001)significant association with T1DM [33]
Association of some other genes including osteopontin(rs1126772 polymorphism) integrin 1205724 (rs1449263 polymor-phism) CD44 (rs8193 polymorphism) and TGF120573 (trans-forming growth factor) (+915CG polymorphism) was alsoinvestigated in 2 studies and no significant relation wasobserved between these variants and T1DM [23 29]
322 MODY In this category only one study was found [34]and the association of Val255Met polymorphism of HNF120572and diabetes was investigated in 101 subjects includingMODY subjects their relatives and healthy controls [34]Thestudy was designed as a case control association study andPCR-RFLP and direct sequencing was used for genotyping
of variants Val255Met mutation in this investigation wasobserved in MODY subjects and their relatives but not incontrol group
323 T2DM Related Genes In this subgroup 42 studieswere assessed and all of them were designed as case controlassociation studies [22 35ndash68 70ndash75] except for one whichwas cross sectionally designed [69] In 33 studies PCR- RFLPwas used for genotyping [22 36ndash38 40ndash54 56 58ndash61 63ndash66 69 72ndash75] In 5 of them PCR was used [35 57 62 70 71]and the remaining studies PCR-SCA [39] real-timePCR [55]ARMS-PCR [66] Gap PCR [67] and CSGE (conformation-sensitive gel electrophoresis) sequencing [68] as the genotyp-ing method were applied
Association between two polymorphisms of TCF7L2including rs7903146 (CT) and rs12255372 (GT)was assessedin three studies [38 48 53] In one study investigatingrs7903146 (CT) in 466 subjects significant difference in thefrequency of CC and CT genotypes was observed betweenT2DM and control group (119875 = 0045) [38] However inanother study this polymorphism showed a positive signifi-cant associationwith TT genotype in T2DM (119875 = 0008) [53]Investigation of rs12255372 (GT) polymorphism of TCF7L2in another study showed that among 491 subjects there wasa positive significant association between TT carriers andT2DM (119875 = 0014) [48]
Investigating the association of calreticulinwith T2DM in650 subjects showed two mutations only in case group 9 bpdeletion of 397ndash399 codons and GgtT mutation at IVSII-142[39]
Association of estrogen receptor 120572 and its PvuII(PPPppp) and XbaI(XXXxxx) polymorphism with T2DM intwo studies was assessed [40 49] In one study the significantassociation of PvuII and XbaI polymorphisms with T2DMwas observed (119875 = 0014 and 119875 = 0002 resp) [40] Inanother study it was revealed that pooled Pp+pp and XX+xxmale carriers have positive significant associationwithT2DM(119875 = 0001 and 119875 = 0026 resp) [49]
Association of Pro12Ala polymorphism of PPAR120574 withT2DMwas investigated in three studies [41 69 75] Negativesignificant association of AlaAla genotype with T2DM wasobserved in two studies (119875 = 0003) [41 75] AlaPro carrierswere shown to be positively associated in one study [41] andnegatively associated in another study [75] with T2DM (119875 lt0001 and 119875 = 0003 resp) However in the third studyno significant association was observed between Pro12Alapolymorphism of PPAR120574 and T2DM [69]
Association of different polymorphisms of ApoAI withT2DM was investigated in two studies [43 72] In one studyinvestigation of MSPI polymorphism showed no significantassociation with T2DM [43] In another study it was shownthat G-75A polymorphism of ApoAI was not associated withT2DM while a significant association was found betweenC+83T polymorphism and T2DM (119875 = 0028) [72]
Two studies assessed the association of minus156GgtC poly-morphism of CXCL5 with T2DM [44 65] In one studypositive significant association of GC carriers (119875 = 0006)and negative association of GG carriers (119875 = 001) was foundbetween diabetic patients and healthy controls [44] and
14 Journal of Diabetes Research
in another study positive significant association was foundbetween GC or CC carriers and T2DM (119875 = 0009) [64]
Adiponectin and its association with T2DM were inves-tigated in two studies [56 73] In one study two variantsincluding +45TG and minus11391GA were investigated but nosignificant relation was found between these two polymor-phisms and T2DM [56] However in another study investi-gating +45TG polymorphism of adiponectin it was revealedthat nonobese T2DM subjects had significantly higher TTgenotype (119875 = 004) [73]
In one study that investigated insulin receptor gene thefollowing mutations were found only in T2DM 511CgtA514TgtG 586 and 628TgtA on exon 2 694GgtC 680GgtA onexon 3 1627AgtT on exon 8 ATgtTG on intron 9 2007CgtCTon exon 9 2595CgtCT and 2669GgtCG on exon 13 2706 and2717CgtG 2752CgtT and 2753CgtG on exon 14 and 3471TgtAand 3516TgtG on exon 19 These mutations were not seen incontrol subjects [68]
Other variants which had significant association withT2DM included haptoglobin (allele 2-2) leptin (G-2548Apolymorphism) paraoxonase 2 (Ser311Cys polymorphism)GST (glutathione-S-transferase) M1 and GSTM1GSTT1interaction calpain-10 (SNP (single nucleotide polymor-phism) 43) IRS-1 (G972R polymorphism) and IRS-2(G1057D polymorphism) VDR (vitamin D receptor) (TaqIpolymorphism) KCNJ11 (E23K polymorphism) eNOS(endothelial nitric oxide synthase) VNTR (intron 4 ab pol-ymorphism) resistin (minus420CG polymorphism) and ACE(InsertionDeletion) [35ndash37 45 47 50 55 57 58 64 70]
In contrast to above variants CTLA4 (+49AG poly-morphism) HNF-1120572 (Ala98Val polymorphism) GLP-1R(glucagon-like peptid 1 receptor) (Thr149Met polymor-ohism) SLC30A8 (Arg325Trp polymorphism) GSTP1(Ile105Val polymorphism) glucokinase (minus30GA polymor-phism) SDF-1120573 (stromal derived factor -1 120573) (G801A poly-morphism) ApoE (apolipoprotein E) ENPP1 (ectoenzymenucleotide pyrophosphate phosphodiesterase 1) (K121Q poly-morphism) SUMO4 (small ubiquitin-like modifier 4)Met55Val polymorphism) MTHFR (C677T polymorphism)UCP2 (uncoupling protein 2) (minus866GA polymorphism)5HTTLPR IL-4 (minus590CT polymorphism) IFN-120574 (inter-feron 120574) (+874TA polymorphism) CCR5 (C-C chemokinereceptor type 5) (12057532mutation) HFE (hemochromatosisgene) (H63D C282Y PTPN1 (protein tyrosin Phosphatase1B)minus51delA minus451AgtG minus467TgtC minus1023CgtA minus1045GgtAminus1286 3 bp del ACA minus1291 9 bp del CTAGACTAA poly-morphisms) were not significantly associated with T2DM[22 42 46 50ndash52 54 59ndash63 66 67 71 74]
324 Genes Related to Insulin Resistance In this subgroupfour studies were assessed and all were designed as case-control association studies Three studies used PCR-RFL [7678 79] and one study used real-time PCR [77] for genotyping
The studies assessed in this subgroup showed a positiveassociation of TG carriers of +45TG polymorphism ofadiponectin (119875 = 0032) and Ala allele carriers of Pro12Alapolymorphism of PPAR120574 (119875 = 0036) with T2DM [76 77]A positive significant association of ff carriers of VDR wasalso shown (FokI polymorphism) (119875 = 002) and negative
association of 148insG carriers of PTPN1 (148insG polymor-phism) (119875 = 0041) with insulin resistance index [7879] However no significant association was shown betweenadiponectin receptor-2+795GA and T2DM [76]
325 Genes Related to Cardiovascular Disease in DiabetesDesign of all 11 studies in this subgroup was case-controlassociation study [80ndash84 86ndash90] except one study which wasdesigned as cross sectional [85] PCR-RFLP was used in all ofthem for genotyping [80ndash88 90] except in one study whichused ARMS-PCR method [89]
Paraoxonase 1 (163TA polymorphism) was the only vari-ant in this subgroup which was not significantly associatedwith atherosclerosis risk in T2DM [80] Investigation ofanother polymorphism of Paraoxonase 1 (Q192R) revealedthat diabetics with CAD had significant increase in RRgenotype (119875 lt 005) [81]
Investigating B1 and B2 alleles of CETP TaqI B allele in400 subjects showed that pooling of B1B1+B1B2 and B1B1genotypes had significant association with T2DM and CAD(119875 lt 001) On the other hand assessing the G894T poly-morphism of eNOS showed positive significant associationbetween TG and TT carriers and CAD (119875 lt 005) It was alsoshown that concomitant presence of NOS3 T allele and CEPTB1 allele was significantly associated with T2DM (119875 = 0004)and CAD (119875 = 0002) [83]
Investigation of apolipoprotein E (E2 E3 and E4) allelesshowed the association of E2 and E4 alleles with CAD(119875 lt 0001) [84 87] Also it was shown that interactionof butyrylcholinesterase (BChE K) and apolipoprotein E(ApoE) was associated significantly with CAD and diabetesApoE4BChE K had significant association with lipid profilesas well (119875 lt 005) [87]
Adiponectin +276GT and +45TG were significantlyassociated with CAD (119875 = 0023 and 0033 resp) [82] whileinvestigating minus1612 5A6A polymorphism of MMP-3 (matrixmetalloproteinase 3) showed a significant association withCAS (coronary artery stenosis) (119875 = 0008) [86]
In addition A1166C polymorphism of AT1R (angiotensinI receptor) and minus420CG polymorphism of resistin in dia-betic patients with CAD revealed significant association withdiabetes 119875 = 001 and 119875 = 0009 respectively [84 85]
Another study showed insertion(I)deletion(D) polymor-phismof angiotensin converting enzyme (ACE)DDgenotypewas significantly associated with higher blood pressure (119875 =0026) [89]
Factor V Leiden (G1691A polymorphism) prothrombin(G20210A polymorphism) and MTHFR (methylenetetrahy-drofolate reductase) (C677T polymorphism) were the vari-ants which were not significantly associated with CAD andT2DM in this subgroup [88]
326 Genes Related to Diabetic Nephropathy All of 15 studiesin this subgroup were designed as case-control associationstudies [91ndash106] In 7 studies PCR-RFLP was used forgenotyping [92ndash95 99 102 103] in four studies PCRwas used[98 101 104 105] and in 4 of them both PCR and PCR-RFLPwere used [91 96 97 100]
Journal of Diabetes Research 15
Studying the association of 163AG polymorphism ofSUMO4 showed a positive significant association betweenAA carriers and diabetic nephropathy (119875 lt 005) [93]
Studying the interaction of eNOS4ab and G894Trevealed positive significant association between 4a or 894Tallele carriers and macro- and microalbuminuria (119875 = 001119875 = 002 resp) [91] It was observed that the interaction ofeNOS (G894T polymorphism) andACE (ID alleles) was sig-nificantly associated with more frequent macroalbuminuria(119875 = 0035) [97]
It has also been shown that interaction of eNOS (G894Tpolymorphisms) and MTHFR (C677T and A1298C poly-morphisms) eNOS T1298 C and eNOS T677 T carriershad positive significant association with macroalbuminuriaIn addition significant association of eNOS GT+TT carrierswith lipid profile (119875 lt 005) was shown in this study [99]
C677T andA1298C polymorphisms ofMTHFRwere alsoinvestigated in another study revealing that 677T 1298Cand 677T1298C carriers were significantly associated withmacroalbuminuria (119875 lt 0001) Positive significant asso-ciation when pooling CT+TT genotypes and 677T1298Cwas also found with microalbuminuria (119875 lt 0001) [103]Investigating the interaction of MTHFR (A1298C C677Tpolymorphisms) and ACE (ID alleles) showed a positivesignificant association of ACE D677T (119875 = 0035) and ACED1298C (119875 = 0012) genotypeswithmacroalbuminuria [96]
ACE (ID alleles) polymorphisms were investigated inthree studies In one study positive significant association(119875 lt 001) between DD carriers and progression but notdevelopment of albuminuria was observed [104] In anotherstudy in nephropathic subjects association of DD carriersand T2DM (119875 = 0006) but not nephropathy was revealed[105] However another study did not show significant asso-ciation of ACE with macroalbuminuria [98] Interaction ofACE (ID alleles) with Factor V Leiden (G1691A polymor-phism) was not significant [100]
Association of interleukins including IL-4 and IL-10 withdiabetic nephropathy was also investigated in two studiesStudy of minus592CA polymorphism of IL-10 revealed positivesignificant association between CC carriers and nephropathy(119875 = 0001) [94] and study ofminus590CTpolymorphismof IL-4revealed positive significant association between CT carriersand nephropathy (119875 lt 0001) [101]
Other significant associations between variants and dia-betic nephropathy included AT2R (angiotensin II recep-tor) (minus1332GA polymorphism) VEGF (vascular epitheliumgrowth factor) (+405GC polymorphism) and VDR (TaqIpolymorphism) [92 95 102] ApaI polymorphism of VDRwas not significantly associated with diabetic nephropathy[102]
327 Genes Related to Diabetic Retinopathy All of the 3studies in this subgroup were conducted as case-controlassociation studies [106ndash108]
Investigating nullpositive genotype of GSTM1 in a studywhich used ARMS-PCR for genotyping revealed that nullgenotype is significantly associated with diabetic retinopathy(119875 lt 005) [106] This result was confirmed in another study
by using multiplex PCR as genotyping [107] although nosignificant association between GSTT1 and retinopathy wasfound in this study [107]
Investigating +405GC polymorphism of VEGF alsorevealed positive significant association between GG carriersand diabetic retinopathy (119875 = 0005) [108]
328 Genes Related to Diabetic Foot Ulcer In this subgrouponly one study was found [109] which was case-controldesigned and used ARMS-PCR for genotyping In this studyassociation of minus7CT and minus2578CA polymorphisms ofVEGF with diabetic foot ulcer (DFU) was investigated and apositive significant association betweenAA carriers andDFU(119875 = 003) was observed But no significant association wasfound between minus7CT of VEGF and DFU [109]
4 Discussion
Diabetes mellitus is the eighth most frequent disease leadingcause of death throughout the world and now ranks the fifthfollowing communicable diseases cardiovascular diseasecancer and injuries [110] Prevalence of diabetes mellitus isincreasing worldwide [6]
Type 2 diabetes is the most frequent type of diabetesmellitus [110 111] Multiple genes and environmental factorsaffect the prevalence of T2DM Systematic review and meta-analysis studies have assessed the association between dif-ferent genes and T2DM Glutathione-S-transferase includingGSTMI GSTM1 and GSTP1 are important genes and theirassociation with diabetes has been investigated in two meta-analysis studies [112 113] It was revealed that null genotypeof both GSTM1 and GSTT1 could be as a risk factor fordiabetes while no significant association was found betweenGSTP1 and diabetes [112 113] These results are in linewith our finding and confirming the association of the nullgenotype of GSTT1 and GSTM1 with T2DM in Iranianpopulation [50] The relation between GSTT1 and GSTM1and diabetic retinopathy has also been shown in Iranianpopulation [106 107]
MTHFR is another important gene in association withT2DM and other related complications No associationof C677T polymorphism of MTHFR gene was found inAfricans Asians and Caucasians [114] MTHFR is a genewhich is involved in DNA methylation and synthesis andregulated folate activity It has been reported that mutanthomozygote and heterozygote of C677T polymorphism ofMTHFR increase plasma homocysteine which is an impor-tant factor leading to diabetic nephropathy (DN) and as aresult C677T polymorphism of MTHFR can be associatedwith the development of DN In Caucasians this associationhas also been observed [115] In Iranian population in linewith other populations no significant association was foundbetween MTHFR polymorphisms and T2DM [63] althoughsignificant association of 677T and 1298C alleles with diabeticnephropathy was observed [87] Interaction of two polymor-phisms and also interaction of MTHFR polymorphisms withother genes such as ACE and eNOS showed an associationwith development of DN [96 99]
16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
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Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
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Gastroenterology Research and Practice
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Journal of Diabetes Research 5
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Masou
detal2007
[29]
TGF120573
+915C
G75
T1DM
and88
healthy
lt30
yrM
FTehran
Case
control
PCR-SSP
Non
significance
Masou
detal2007
[30]
IL-12+1188A
C75
T1DM
and88
healthy
lt30
yrM
FTehran
Case
control
PCR-SSP
Sign
ificant
associationbetween
AAandAC
geno
type
andT1DM
(P=0035)
Mojtahedi
etal2006
[31]
IL-18minus607A
C
minus137C
G112T1DM
and194no
n-DM
lt15
andgt15yrM
FSh
iraz
Case
control
PCR-SSP
minus137C
Candminus607A
Aminus137C
Csig
nificantassociatio
nwith
T1DM
inon
setgt
15yr
(P=0027)
Mojtahedi
etal2005
[32]
CTLA
-4+49AG
109T1DM
and331h
ealth
y0ndash
37yrM
FSh
iraz
Case
control
PCR-SSP
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenAG
carriersandT1DM
(P=000)
(ii)N
egatives
ignificant
associationbetweenAAcarriers
andT1DM
(P=000)
Zamanietal2005
[33]
CD4A2
ndashA9
92T1DM
and108healthy
gt35
yrM
FTehran
Case
control
PCR
Negatives
ignificantassociatio
nbetweenA3alleleandT1DM
(P=0025)
Positives
ignificantassociatio
nbetweenA5alleleandT1DM
(P=0001)
MODY
Tagh
avietal2009
[34]
HNF120572
Val255M
et30
MODY21
relativ
esand
50healthy25ndash35y
rMF
Mashh
adCa
secontrol
PCR-FL
Psequ
encing
Them
utationwas
foun
din
patie
ntsa
ndrelatives
butn
otin
controls
T2DM
andcomplications
Ahm
adietal2013
[22]
CTLA
-4+49AG
Said
above
Said
above
Said
above
Said
above
Non
significance
Amiri
etal2013
[35]
Haptoglob
in1-
12-12-2
134T2
DM
with
MVC
s71
T2DM
with
outM
VCs
46ndash72y
rMF
Sari
Case
control
PCR
Hp2-2
high
lysig
nificantfor
T2DM
(P=005)
And
alib
etal2013
[36]
Paraoxon
ase2
Ser311Cys
100T2
DM
and100healthy
51yrM
FIsfahan
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
CysCy
sand
CysSerc
arrie
rsand
negativ
esignificantassociatio
nof
SerSerc
arrie
rswith
T2DM
(Plt005)
Kohanetal2013
[37]
LeptinG
-2548A
100T2
DM
and100healthy
44ndash6
6yrMF
Arsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersandT2
DM
(P=000
4)
Alamietal2013
[38]
TCF7L2
rs7903146
(CT)
233T
2DM
and233controls
gt40
yrM
FGorgan
Case
control
PCR-RF
LPCC
andCT
geno
typessignificant
differenceb
etweenT2
DM
and
controls(P
=0045)
Mahmazietal2013
[39]
Calre
ticulin
120T2
DM
and530controls
43ndash6
6yrMF
Zanjan
Case
control
PCR-SC
A9b
pdeletio
nof
397ndash399codo
nsGgtTmutationatIV
SII-142in
T2DM
notincontrols
6 Journal of Diabetes ResearchTa
ble1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Moh
ammadietal2013
[40]
(i)ER120572PvuII(PPPp
pp)
(ii)E
R120572XbaI(XX
Xxxx)
174T2
DM
and174ND
35ndash6
5yrMF
Jahrom
Case
control
PCR-RF
LP
(i)Sign
ificant
associationwith
T2DM
(P=0014)
TC(P
=0007)and
TG(119875=0005)fem
alec
arrie
rs(ii)S
ignificantassociatio
nwith
T2DM
(119875=0002)TC
(119875=0003)andTG
(119875=0009)
femalec
arrie
rs
Motavallianetal2013
[41]
PPAR-1205742Pro12A
la100T2
DM
and100healthy
51yrM
FIsfahan
Case
control
PCR-RF
LP
Negatives
ignificantassociatio
nbetweenAlaA
lacarriers
(119875lt0001)a
ndpo
sitive
significantassociatio
nbetween
AlaPro
carrierswith
T2DM
(119875lt0001)
Sepahi
etal2013
[42]
HNF-1120572Ala98Va
lGLP
-1RTh
r149Met
100T2
DM
and50
healthy
controlsle35
andgt35
yrM
FMashh
adCa
secontrol
PCR-RF
LPNon
significance
Sheikh
haetal2013
[43]
APO
A1M
SP-I
200T2
DM
and200healthy
418yrM
FYazd
Case
control
PCR-RF
LPNon
significance
Yagh
oubietal2013
[44]
CXCL
5minus156GgtC
100T2
DM54y
rand
100healthy
56yrM
FArdabil
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GCcarriers(119875=0006)a
ndnegativ
esignificantassociatio
nof
GGcarrierswith
T2DM
(P=001)
Bahreini
etal2012
[45]
Calpain-10SNP4
3(AG)
102T2
DM
and100healthy
40ndash70y
rM
EastAzerbayjan
Case
control
PCR-RF
LPGallelea
srisk
factor
ofT2
DM
(P=0037)
Derakhshanetal2012
[46]
SDF-1120573G
801A
200T2
DM
and200healthy
40yrM
FRa
fsanjan
Case
control
PCR-RF
LPNon
significance
Haghani
etal2012
[47]
(i)IRS-1G
972R
(ii)IRS
-2G
1057D
336T2
DM
and341h
ealth
y44
ndash63y
rMF
Ilam
andKe
rmanshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
GR(P
=0001)andRR
(119875=00001)carrie
rswith
T2DM
(ii)P
ositive
significant
associationbetweenGDcarriers
andT2
DM
(P=0016)
Alamietal2012
[48]
TCF7L2
rs12
255372
(GT)
236T2
DM
and255healthy
gt37
yrM
FGorgan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersandT2
DM
(P=0014)
Meshk
anietal2012
[49]
(i)ER120572PvuII(PPPp
pp)
(ii)E
R120572XbaI(XX
Xxxx)
155T2
DM
and377controls
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
pooled
Pp+pp
malec
arrie
rs(P
=0001)with
T2DM
(ii)P
ositive
significant
associationof
pooled
XX+
xxmalec
arrie
rs(P
=0026)
with
T2DM
Journal of Diabetes Research 7
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Moasser
etal2012
[50]
GST
M1p
resentnull
GST
T1presentnull
GST
P1Ile105Va
l
171T
2DM
and169healthy
25ndash6
5yrMF
Shira
zCa
secontrol
PCR-RF
LP
GST
M1-n
ull(P=0016)
and
interactionof
GST
M-nullG
STT1-null
(119875=0022)significant
associationwith
T2DM
Moh
addese
tal2012
[51]
SLC3
0A8Arg325Trp
125T2
DM
and125controls
40ndash70y
rMF
Azarbayjan
Case
control
PCR-RF
LPNon
significance
Oladi
etal2012
[52]
Glucokinaseminus30GA
542subjects
18ndash6
5yrMF
Mashh
adCr
osssectio
nal
PCR-RF
LPNon
significance
Palizbanetal2012
[53]
TCF7L2
rs7903146
(CT)
110T2
DM
and80
healthy
46ndash6
7yrMF
Isfahan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersandT2
DM
(P=0008)
Tabatabaei-M
alazyetal2012
[54]
ApoE
E3-E3
E2-E3
E4-E3
156T2
DM
and155healthy
25ndash6
5MF
Tehran
Case
control
PCR-RF
LPNon
significance
Ghasemietal2012
[55]
KCNJ11
E23K
358T2
DM
and388healthy
41ndash6
9yrMF
Rasht
Case
control
Realtim
ePCR
Positives
ignificantassociatio
nbetweenKK
carriersandob
ese
T2DM
(P=0037)
Ranjbare
tal2011[56]
Adipon
ectin
+45TG
minus113
91GA
244T2
DM
and99
healthy
37ndash6
5yrMF
Rafsanjan
Case
control
PCR-RF
LPNon
significant
Mehrab-Moh
seni
etal2011[57]
eNOSVNTR
intro
n4ab
220T2
DM
and96
healthy
53plusmn15yrM
FRa
fsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenaa
orab
carriersand
T2DM
(P=002)
Nosratabadi
etal2011[58]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DM
and100healthy
40yrM
FRa
fsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandT2
DM
(Plt0001)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandT2
DM
Saberietal2011[59]
ENPP
1K121Q
155T2
DM
and377healthy
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LPNon
significance
Fallahetal2010
[60]
SUMO4Met55Va
l(16
3AG
)50
T2DM
and50
healthy
25ndash4
5yrMF
Tehran
Case
control
PCR-RF
LPNon
significance
Heidarietal2010
[61]
UCP
2minus866G
A75
T2DM75NDob
esea
nd75
NDno
nobese35ndash76
yrM
FTehran
Case
control
PCR-RF
LPNon
significance
Nazem
etal2010
[62]
5HTT
LPRSSSLLL
90T2
DM
and90
healthy
54ndash6
6yrMF
Shira
zCa
secontrol
PCR
Non
significance
Bazzaz
etal2010
[63]
MTH
FRC677T
401T
2DM74NDob
esea
nd207
NDno
nobese30ndash
63yrM
FTehran
Case
control
PCR-RF
LPNon
significance
Emam
gholipou
retal2009
[64]
resistin
minus420C
G47
T2DM
and66
healthy
58plusmn9y
rMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandT2
DM
(P=000
9)
Hasani-R
anjbar
etal2009
[65]
CXCL
5minus156G
C230T2
DM
and120healthy
40ndash6
3yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGCor
CCcarriersand
T2DM
(P=000
4)
8 Journal of Diabetes ResearchTa
ble1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
KazemiA
rababadi
etal2009
[66]
IL-4minus590C
TIFN-120574+874T
A160T2
DM
and160healthy
38plusmn9y
rMF
Rafsanjan
Case
control
PCR-RF
LPARM
S-PC
RNon
significance
Arababadi
etal2009
[67]
CCR5
12057532mutation
200T2
DM
and300healthy
40plusmn9y
rMF
Rafsanjan
Case
control
Gap-PCR
Non
significance
Kazemietal2009
[68]
INSR
128T2
DMgt
40yrM
FTehran
Case
control
PCR
CSGE
sequ
encing
Follo
wingmutations
werefou
ndon
lyin
T2DM
511CgtA514Tgt
G586and
628TgtAon
exon
2694GgtCand680GgtAon
exon
31627AgtTon
exon
8ATgtTG
onintro
n9
2007Cgt
CTon
exon
92595Cgt
CTand2669GgtCGon
exon
132706
and2717Cgt
G2752CgtT
2753Cgt
Gonexon
143471Tgt
Aand3516Tgt
Gon
exon
19
Mirz
aeietal2009
[69]
PPAR120574
2Pro12A
la78
norm
al78ob
ese78
T2DM
and78
obeseT
2DM25ndash64
yr
MF
Tehran
Crosssectio
nal
PCR-RF
LPNon
significance
Nikzamiretal2008
[70]
ACEinsertion(I)
deletion(D
)170T2
DM
and144healthyMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(P=002)
Sharifi
etal2008
[71]
HFE
H63D
C282Y
101T
2DM
and101h
ealth
y55plusmn11yrM
FZa
njan
Case
control
PCR
Non
significance
Besharatietal2007
[72]
(i)Ap
oA-IG
-75A
(ii)A
poA-
IC+8
3T215subjects26ndash
64yrM
FTehran
Crosssectio
nal
PCR-RF
LP
(i)Non
significantassociatio
nbetweenG-75A
carriersand
T2DM
(ii)P
ositive
significant
associationbetweenCT
carriers
andT2
DM
(P=0028)
Hasani-R
anjbar
etal2007
[73]
Adipon
ectin
+45TG
80T2
DM
obese72
T2DM
nono
beseand
70healthy
25ndash6
4yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersand
nono
bese
T2DM
(P=004)
Meshk
anietal2007
[74]
PTPN
1minus51delA
minus451AgtGminus467TgtC
minus1023Cgt
Aminus1045GgtAminus1286
3bpdel
ACAminus1291
9bpdel
CTAG
ACTA
A
174T2
DM
and412healthy
23ndash79MF
Tehran
Case
control
PCR
sequ
encing
PCR-RF
LPNon
significance
Meshk
anietal2007
[75]
PPAR120574
Pro12Ala
412T2
DM
and284healthy
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LPNegatives
ignificantassociatio
nbetweenProAlaor
AlaA
lacarriersandT2
DM
(P=0003)
Journal of Diabetes Research 9
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
T2DM
patie
ntsa
ndinsulin
resistance
Nam
varanetal2012
[76]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin
receptor-2+795G
A
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTG
carriersandT2
DM
(P=0032)
(ii)N
onsig
nificantassociatio
nbetween+7
94GA
carriersand
insulin
resistance
Nam
varanetal2011[77]
PPAR120574
Pro12Ala
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
Realtim
ePCR
Positives
ignificantassociatio
nbetweenAlaallelecarriersand
T2DM
(P=0036)
Hossein-nezhadetal2009
[78]
VDRFokI
(FFFfff
)105T2
DM55plusmn10yrM
FTehran
Case
serie
sPC
R-RF
LPPo
sitives
ignificantassociatio
nbetweenffcarriersandinsulin
resistanceind
ex(P
=002)
Moo
sapo
oretal2007
[79]
PTPN
1148insG
71T2
DM
and264ND
20ndash80y
rMF
Tehran
Case
control
PCR-RF
LP
Negatives
ignificantassociatio
nbetween148insGcarriersand
insulin
resistanceind
ex(119875=0041)
T2DM
patie
ntsa
ndheartd
iseases
Bayatm
akoo
etal2013
[80]
Paraoxon
ase116
3TA
(L55M)
105CA
DD
Mand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPNon
significance
Bayatm
akoo
etal2012
[81]
Paraoxon
ase1575Ggt
A(Q
192R
)105DMCADand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenRR
carriersand
CADD
M(Plt005)
Estegh
amatietal2012
[82]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin+276G
T114
CADD
Mand127DM
42ndash71yrMF
Tehran
Case
control
PCR-RF
LP
(i)Negatives
ignificant
associationbetween45TT
carriersandCA
D(P
=0033)
(ii)P
ositive
significant
associationbetween276G
GcarriersandCA
D(P
=0023)
Rahimietal2012
[83]
eNOSG8
94T
CETP
B1
102CA
DD
M105
CADN
D101
DMand
92ND45ndash66
yrM
FKe
rmanshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
concom
itant
presence
ofNOS3
TalleleandCE
PTB1
allelewith
T2DM
(P=000
4)andCA
D(119875=0002)
Assalietal2011[84]
AT1RA116
6C145CA
DD
Mand164CA
D
lt50
andge50
yrM
FMashh
adCa
secontrol
PCR-RF
LPPo
sitives
ignificantassociatio
nof
ACandCC
carrierswith
DM
(119875=001)
Emam
gholipou
retal2009
[85]
Resistin
minus420C
G113CA
Dwith
andwith
outD
M
58plusmn9yrM
FTehran
Crosssectio
nal
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDM
(119875=0009)
10 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Fallahetal2010
[86]
MMP-3minus1612
5A6A
305CA
DD
Mand313DM
61plusmn9yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetween6A
6AcarriersandCA
S(P
=0008)
Vaisi-Raygani
etal2010
[87]
BChE
KG1
615A
APO
EE2
E3E4
118DM162
CADN
D172
DMCADand
179healthy
42ndash6
8yrMF
Kerm
anshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GAA
Aand
E4carrierswith
CADandDM
(Plt005)
Positives
ignificantassociatio
nof
BChE
KAp
oE4carrierswith
CADand
DM
(Plt005)
Sign
ificant
associationof
BChE
KAp
oE4with
lipid
profi
le(119875lt005)
Rahimietal2009
[88]
Factor
VLeidenG
1691A
Prothrom
binG2
0210A
MTH
FRC677T
65CA
DD
M52CA
DN
Dand
59healthy46
064y
rMF
Kerm
anshah
Case
control
PCR-RF
LPNon
significance
Nakhjavanietal2007
[89]
ACEID
82DM
with
hypertensio
nand87
DM
with
outh
ypertension
49ndash6
3yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
hypertensio
n(P
=0026)
Vaisi-Raygani
etal2007
[90]
Apolipop
roteinE2E3
E4
152CA
DD
M262
CADN
D
and300healthy35ndash73y
rMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nof
E2andE4
allelec
arrie
rswith
CAD(Plt0001)
T2DM
patie
ntsa
ndneph
ropathy
Rahimietal2013
[91]
eNOS4abG
894T
63T2
DMm
icroalbu
minuria
57T2
DMm
acroalbu
minuria
52T2
DMnormoalbum
inuria
121D
Nand
101h
ealth
y45ndash6
6yrMF
Kerm
anshah
Case
control
PCR
PCR-RF
LP
Positives
ignificantassociatio
nof
4aor
894T
allelecarriersand
macro-(P=001)o
rmicroalbu
minuria(P
=002)
Rahimietal2013
[92]
AT2R
minus1332GA
28T2
DMm
icroalbu
minuria
22T2
DMm
acroalbu
minuria
20T2
DMnormoalbum
inuria
and112healthy43ndash6
3yrMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(P
=0016)
Shahsavare
tal2013
[93]
SUMO4163A
G(M
55V)
50T2
DD
Nand50
T2DM
non-DN25ndash45
yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(Plt005)
Arababadi
etal2012
[94]
IL-10minus592C
A100T2
DMnon
-DN100
T2DMD
Nand100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDN
(119875=0001)
Journal of Diabetes Research 11
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2012
[95]
VEG
F+4
05G
C255T2
DMm
icroalbu
minuria
and235T2
DMnon
albu
minuric
50ndash6
7yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersand
albu
minuria(P
=0002)
Rahimietal2012
[96]
MTH
FRA1298C
C677T
ACEID
72T2
DMM
icAlb
68T2
DMM
acAlband72
T2DMnon
-DN46ndash
65yrM
FKe
rmanshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nof
ACED677T(P
=0035)
and
ACED12
98C(P
=0012)
carrierswith
macroalbu
minuria
Rahimietal2012
[97]
eNOSG8
94T
ACEID
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nbetweenAC
EDcarriersand
macroalbu
minuria(P
=0035)
Feleh
garietal2011[98]
ACEID
68T2
DMm
acroalbu
minuria
and72
T2Dmnormoalbum
inuria
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR
Non
significance
Jafarietal2011[99]
eNOSG8
94T
MTH
FRC677TA
1298C
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
eNOST1298
CandeN
OS
T677Tcarrierswith
macroalbu
minuria(Plt005)
(ii)S
ignificantassociatio
nof
eNOSGT+
TTcarrierswith
lipid
profi
le(Plt005)
Rahimietal2011[100]
ACEID
Factor
VLeidenG
1691A
217mean55both
Kerm
anshah
Case
control
PCR
PCR-RF
LPNon
significance
Arababadi2010[101]
IL-4minus590C
T100T2
DMD
Nand150healthy
33ndash4
7yrMF
Rafsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenCT
carriersandDN
(119875lt0001)
Nosratabadi
etal2010
[102]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DMnon
-DN100
T2DMD
Nand
100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandDN
(119875=0012)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandDN
Rahimietal2010
[103]
MTH
FRC677TA
1298C
72T2
DMm
icrolbum
iunira
68T2
DMm
acroalbu
minuria
and72
T2DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
677T1298C
and677T
1298C
carrierswith
macroalbu
minoria
(Plt0001)
(ii)P
ositive
significant
associationof
CT+T
Tand
677T
1298Ccarrierswith
microalbu
minuria(Plt0001)
12 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2009
[104]
ACEID
129T
2DMm
icrolbum
iunira
48T2
DMm
acroalbu
minuria
and145T
2DMnormoalbum
inuria
594plusmn85y
rMF
Tehran
Crosssectio
nal
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
progressionof
albu
minuria
(119875lt001)b
utno
tits
developm
ent
Nikzamiretal2006
[105]
ACEID
85T2
DMD
N85T2
DMnon
-DN
and91
healthy37ndash6
7yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(119875=0006)b
utno
tDN
T2DM
patie
ntsa
ndretin
opathy
Abbasietal2013
[106]
GST
M1n
ullp
ositive
80DRand80
healthy
30ndash70y
rMF
Rasht
Case
control
ARM
S-PC
RNullgenotypes
ignificant
association
Plt005
Dadbinp
oure
tal2013
[107]
(i)GST
M1n
ullp
ositive
(ii)G
STT1nullp
ositive
57DRand58
non-DR
35ndash6
5yrMF
Yazd
Case
control
Multip
lexPC
R
(i)Nullgenotypeo
fGST
M1o
rGST
T1sig
nificantassociatio
n(119875=004)
(ii)N
onsig
nificantassociatio
nof
GST
T1nu
llcarrierswith
DR
Fegh
hietal2011[108]
VEG
F+4
05G
C119
diabeticsw
ithPD
Rand279
diabeticsw
ithNPD
R47ndash6
6yrMF
Ahvaz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersanddiabetic
retin
opathy
(P=0005)
T2DM
patie
ntsa
ndfoot
ulcer
Amolietal2011[109]
(i)VEG
Fminus7C
T(ii)V
EGFminus2578CA
247T2
DM
with
DFU
241
T2DM
with
outD
FUand
98healthy
43ndash6
4MF
Tehran
Case
control
ARM
S-PC
R
(i)Non
significantassociatio
nof
minus7C
Tcarrierswith
DFU
(ii)P
ositive
significant
associationbetweenAAcarriers
andDFU
(P=003)
SNPsin
glenu
cleotid
epo
lymorph
ismT
1DMtype1d
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4T2
DMtype2diabetes
mellitusP
CRp
olym
erasechainreactio
nRF
LPrestrictio
nfragmentlengthpo
lymorph
ismILinterle
ukinSS-PC
Rsequ
ence
specificP
CRV
DR
vitamin
DreceptorT
AP2
transpo
rter
2AT
P-bind
ingcassetteA
RMS-PC
Ram
plificatio
nrefractory
mutationsyste
mPC
RPC
R-SSPPC
Rsin
glespecificprim
erT
GF120573
transform
inggrow
thfactor120573D
Md
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4
MODY
maturity
onsetd
iabeteso
fthe
youn
gHNF-
1120572h
epatocytenu
clear
factor
1120572M
VCm
icrovascular
complicationsT
CF7L
2transcrip
tionfactor
7-lik
e2PC
R-SSCA
PCR
singlestr
andconformationpo
lymorph
ismanalysis
ER120572estr
ogen
receptor120572N
D
nond
iabeticsTC
totalcholesterolTG
trig
lycerid
esP
PAR-1205742peroxisomep
roliferator-activates
receptor120574G
LP-1R
glucagon
-like
peptid
1receptorAPO
apo
lipop
roteinC
XCL5chemokineC
-X-C
motifligand
5SD
F-1120573stro
malderiv
edfactor-1120573IRS
1amp2insulin
receptor
substrate1amp
2GSTglutathione-S-tr
ansfe
raseSLC
30A8solublecarrier3
0A8KC
NJPo
tassium
inwardly-rectify
ingchanneleN
OSendo
thelial
nitricoxidesynthaseVNTR
variablen
umbero
ftandem
repeatsEN
PP1ectoenzymen
ucleotidep
yrop
hosphateph
osph
odieste
rase1SU
MOsmallubiqu
itin-lik
emod
ifier4UCP
2un
coup
lingp
rotein
2MTH
FR
methylenetetrahydrofolateredu
ctaseIFN120574interferon120574C
CR5C-
Cchem
okiner
eceptortype5
INSR
insulin
receptorC
SGE
conformation-sensitive
gelelectroph
oresis
ACE
angiotensin
Icon
vertingenzyme
HFE
hem
ochrom
atosisgenePTP
N1proteintyrosin
Phosph
atase1B
CADcoron
arya
rteryd
iseaseCE
TPcho
leste
ryleste
rtransferp
roteinA
T1R
angiotensin
IreceptorMMP3
matrix
metalloproteinase
3CA
Scoronary
artery
steno
sisB
ChEK
Butyrylcho
linesteraseK
DNdiabetic
neph
ropathyAT
2Rang
iotensin
IIreceptorV
EGFvascularepith
elium
grow
thfactorD
Rdiabeticretin
opathy
PDR
proliferativ
ediabetic
retin
opathy
NPD
Rno
n-PD
RDFU
diabetic
foot
ulcer
Journal of Diabetes Research 13
321 T1DM Related Genes All the studies in this subgroupincluding 12 studies [22ndash33] were in a case control studydesign using PCR (polymerase chain reaction) [33] PCR-RFLP (restriction fragment length polymorphism) [22 2325 26 32] PCR-SSP (single specific primer) [24 28ndash32]and ARMS-PCR (amplification refractory mutation systemPCR) [27] method In all studies both men and women wereincluded and the overall 2519 subjects were under 40 yearsold
Association of interleukins including IL-18 (interleukin)and IL-12 with T1DM revealed that the minus137CG polymor-phism of IL-18 had significant association with T1DM (119875 =0037 119875 = 00001) while no significant relation was observedbetween minus607AC variant of this gene and T1DM [24 28]Investigating IL-12 also showed that there was a significantassociation between +1188AC polymorphism of this geneand T1DM (119875 = 0035) [30]
In 2 studies the association of +49AG variant of CTLA-4 (cytotoxic T lymphocyte associated antigen 4) was investi-gated and it was revealed that there was a positive significantassociation between AG genotype and T1DM (119875 = 001 119875 lt0001) [22 32] One of these studies also revealed that therewas a negative relation betweenAA genotype and T1DM [32]
Vitamin D receptor (VDR) was investigated in 2 studies[25 26] Both of them assessed the association of FokI BsmIApaI and TaqI variants of VDR with T1DM In one studywhichwas performed on 114 subjects Aa (119875 = 0003) FF (119875 =0008) and Bb (119875 = 0014) genotypes were shown to be pos-itively associated with T1DM but no significant associationwas observed between TaqI polymorphism and T1DM [25]Another study which was performed on 187 subjects showedno significant association between T1DM and FokI BsmIand ApaI However TT genotype was observed to be morefrequent in controls (119875 = 0007) and negatively associatedwith T1DM [26]
Different polymorphisms of TAP2 and their associationwith T1DM were investigated in 191 subjects It was shownthat Ile379Val and Stop687Gln had significant associationwith T1DM (119875 = 0001 and 119875 = 0013 resp) Other variantsof TAP2 (transporter 2 ATP-binding cassette) includingAla565Thr Arg651Cys and Ala665Thr were not associatedwith T1DM significantly [27]
Association of alleles A2ndashA9 of CD4 with T1DM wasassessed in 200 subjects It was revealed that A3 allele hadnegative (119875 = 0025) and A5 had positive (119875 = 0001)significant association with T1DM [33]
Association of some other genes including osteopontin(rs1126772 polymorphism) integrin 1205724 (rs1449263 polymor-phism) CD44 (rs8193 polymorphism) and TGF120573 (trans-forming growth factor) (+915CG polymorphism) was alsoinvestigated in 2 studies and no significant relation wasobserved between these variants and T1DM [23 29]
322 MODY In this category only one study was found [34]and the association of Val255Met polymorphism of HNF120572and diabetes was investigated in 101 subjects includingMODY subjects their relatives and healthy controls [34]Thestudy was designed as a case control association study andPCR-RFLP and direct sequencing was used for genotyping
of variants Val255Met mutation in this investigation wasobserved in MODY subjects and their relatives but not incontrol group
323 T2DM Related Genes In this subgroup 42 studieswere assessed and all of them were designed as case controlassociation studies [22 35ndash68 70ndash75] except for one whichwas cross sectionally designed [69] In 33 studies PCR- RFLPwas used for genotyping [22 36ndash38 40ndash54 56 58ndash61 63ndash66 69 72ndash75] In 5 of them PCR was used [35 57 62 70 71]and the remaining studies PCR-SCA [39] real-timePCR [55]ARMS-PCR [66] Gap PCR [67] and CSGE (conformation-sensitive gel electrophoresis) sequencing [68] as the genotyp-ing method were applied
Association between two polymorphisms of TCF7L2including rs7903146 (CT) and rs12255372 (GT)was assessedin three studies [38 48 53] In one study investigatingrs7903146 (CT) in 466 subjects significant difference in thefrequency of CC and CT genotypes was observed betweenT2DM and control group (119875 = 0045) [38] However inanother study this polymorphism showed a positive signifi-cant associationwith TT genotype in T2DM (119875 = 0008) [53]Investigation of rs12255372 (GT) polymorphism of TCF7L2in another study showed that among 491 subjects there wasa positive significant association between TT carriers andT2DM (119875 = 0014) [48]
Investigating the association of calreticulinwith T2DM in650 subjects showed two mutations only in case group 9 bpdeletion of 397ndash399 codons and GgtT mutation at IVSII-142[39]
Association of estrogen receptor 120572 and its PvuII(PPPppp) and XbaI(XXXxxx) polymorphism with T2DM intwo studies was assessed [40 49] In one study the significantassociation of PvuII and XbaI polymorphisms with T2DMwas observed (119875 = 0014 and 119875 = 0002 resp) [40] Inanother study it was revealed that pooled Pp+pp and XX+xxmale carriers have positive significant associationwithT2DM(119875 = 0001 and 119875 = 0026 resp) [49]
Association of Pro12Ala polymorphism of PPAR120574 withT2DMwas investigated in three studies [41 69 75] Negativesignificant association of AlaAla genotype with T2DM wasobserved in two studies (119875 = 0003) [41 75] AlaPro carrierswere shown to be positively associated in one study [41] andnegatively associated in another study [75] with T2DM (119875 lt0001 and 119875 = 0003 resp) However in the third studyno significant association was observed between Pro12Alapolymorphism of PPAR120574 and T2DM [69]
Association of different polymorphisms of ApoAI withT2DM was investigated in two studies [43 72] In one studyinvestigation of MSPI polymorphism showed no significantassociation with T2DM [43] In another study it was shownthat G-75A polymorphism of ApoAI was not associated withT2DM while a significant association was found betweenC+83T polymorphism and T2DM (119875 = 0028) [72]
Two studies assessed the association of minus156GgtC poly-morphism of CXCL5 with T2DM [44 65] In one studypositive significant association of GC carriers (119875 = 0006)and negative association of GG carriers (119875 = 001) was foundbetween diabetic patients and healthy controls [44] and
14 Journal of Diabetes Research
in another study positive significant association was foundbetween GC or CC carriers and T2DM (119875 = 0009) [64]
Adiponectin and its association with T2DM were inves-tigated in two studies [56 73] In one study two variantsincluding +45TG and minus11391GA were investigated but nosignificant relation was found between these two polymor-phisms and T2DM [56] However in another study investi-gating +45TG polymorphism of adiponectin it was revealedthat nonobese T2DM subjects had significantly higher TTgenotype (119875 = 004) [73]
In one study that investigated insulin receptor gene thefollowing mutations were found only in T2DM 511CgtA514TgtG 586 and 628TgtA on exon 2 694GgtC 680GgtA onexon 3 1627AgtT on exon 8 ATgtTG on intron 9 2007CgtCTon exon 9 2595CgtCT and 2669GgtCG on exon 13 2706 and2717CgtG 2752CgtT and 2753CgtG on exon 14 and 3471TgtAand 3516TgtG on exon 19 These mutations were not seen incontrol subjects [68]
Other variants which had significant association withT2DM included haptoglobin (allele 2-2) leptin (G-2548Apolymorphism) paraoxonase 2 (Ser311Cys polymorphism)GST (glutathione-S-transferase) M1 and GSTM1GSTT1interaction calpain-10 (SNP (single nucleotide polymor-phism) 43) IRS-1 (G972R polymorphism) and IRS-2(G1057D polymorphism) VDR (vitamin D receptor) (TaqIpolymorphism) KCNJ11 (E23K polymorphism) eNOS(endothelial nitric oxide synthase) VNTR (intron 4 ab pol-ymorphism) resistin (minus420CG polymorphism) and ACE(InsertionDeletion) [35ndash37 45 47 50 55 57 58 64 70]
In contrast to above variants CTLA4 (+49AG poly-morphism) HNF-1120572 (Ala98Val polymorphism) GLP-1R(glucagon-like peptid 1 receptor) (Thr149Met polymor-ohism) SLC30A8 (Arg325Trp polymorphism) GSTP1(Ile105Val polymorphism) glucokinase (minus30GA polymor-phism) SDF-1120573 (stromal derived factor -1 120573) (G801A poly-morphism) ApoE (apolipoprotein E) ENPP1 (ectoenzymenucleotide pyrophosphate phosphodiesterase 1) (K121Q poly-morphism) SUMO4 (small ubiquitin-like modifier 4)Met55Val polymorphism) MTHFR (C677T polymorphism)UCP2 (uncoupling protein 2) (minus866GA polymorphism)5HTTLPR IL-4 (minus590CT polymorphism) IFN-120574 (inter-feron 120574) (+874TA polymorphism) CCR5 (C-C chemokinereceptor type 5) (12057532mutation) HFE (hemochromatosisgene) (H63D C282Y PTPN1 (protein tyrosin Phosphatase1B)minus51delA minus451AgtG minus467TgtC minus1023CgtA minus1045GgtAminus1286 3 bp del ACA minus1291 9 bp del CTAGACTAA poly-morphisms) were not significantly associated with T2DM[22 42 46 50ndash52 54 59ndash63 66 67 71 74]
324 Genes Related to Insulin Resistance In this subgroupfour studies were assessed and all were designed as case-control association studies Three studies used PCR-RFL [7678 79] and one study used real-time PCR [77] for genotyping
The studies assessed in this subgroup showed a positiveassociation of TG carriers of +45TG polymorphism ofadiponectin (119875 = 0032) and Ala allele carriers of Pro12Alapolymorphism of PPAR120574 (119875 = 0036) with T2DM [76 77]A positive significant association of ff carriers of VDR wasalso shown (FokI polymorphism) (119875 = 002) and negative
association of 148insG carriers of PTPN1 (148insG polymor-phism) (119875 = 0041) with insulin resistance index [7879] However no significant association was shown betweenadiponectin receptor-2+795GA and T2DM [76]
325 Genes Related to Cardiovascular Disease in DiabetesDesign of all 11 studies in this subgroup was case-controlassociation study [80ndash84 86ndash90] except one study which wasdesigned as cross sectional [85] PCR-RFLP was used in all ofthem for genotyping [80ndash88 90] except in one study whichused ARMS-PCR method [89]
Paraoxonase 1 (163TA polymorphism) was the only vari-ant in this subgroup which was not significantly associatedwith atherosclerosis risk in T2DM [80] Investigation ofanother polymorphism of Paraoxonase 1 (Q192R) revealedthat diabetics with CAD had significant increase in RRgenotype (119875 lt 005) [81]
Investigating B1 and B2 alleles of CETP TaqI B allele in400 subjects showed that pooling of B1B1+B1B2 and B1B1genotypes had significant association with T2DM and CAD(119875 lt 001) On the other hand assessing the G894T poly-morphism of eNOS showed positive significant associationbetween TG and TT carriers and CAD (119875 lt 005) It was alsoshown that concomitant presence of NOS3 T allele and CEPTB1 allele was significantly associated with T2DM (119875 = 0004)and CAD (119875 = 0002) [83]
Investigation of apolipoprotein E (E2 E3 and E4) allelesshowed the association of E2 and E4 alleles with CAD(119875 lt 0001) [84 87] Also it was shown that interactionof butyrylcholinesterase (BChE K) and apolipoprotein E(ApoE) was associated significantly with CAD and diabetesApoE4BChE K had significant association with lipid profilesas well (119875 lt 005) [87]
Adiponectin +276GT and +45TG were significantlyassociated with CAD (119875 = 0023 and 0033 resp) [82] whileinvestigating minus1612 5A6A polymorphism of MMP-3 (matrixmetalloproteinase 3) showed a significant association withCAS (coronary artery stenosis) (119875 = 0008) [86]
In addition A1166C polymorphism of AT1R (angiotensinI receptor) and minus420CG polymorphism of resistin in dia-betic patients with CAD revealed significant association withdiabetes 119875 = 001 and 119875 = 0009 respectively [84 85]
Another study showed insertion(I)deletion(D) polymor-phismof angiotensin converting enzyme (ACE)DDgenotypewas significantly associated with higher blood pressure (119875 =0026) [89]
Factor V Leiden (G1691A polymorphism) prothrombin(G20210A polymorphism) and MTHFR (methylenetetrahy-drofolate reductase) (C677T polymorphism) were the vari-ants which were not significantly associated with CAD andT2DM in this subgroup [88]
326 Genes Related to Diabetic Nephropathy All of 15 studiesin this subgroup were designed as case-control associationstudies [91ndash106] In 7 studies PCR-RFLP was used forgenotyping [92ndash95 99 102 103] in four studies PCRwas used[98 101 104 105] and in 4 of them both PCR and PCR-RFLPwere used [91 96 97 100]
Journal of Diabetes Research 15
Studying the association of 163AG polymorphism ofSUMO4 showed a positive significant association betweenAA carriers and diabetic nephropathy (119875 lt 005) [93]
Studying the interaction of eNOS4ab and G894Trevealed positive significant association between 4a or 894Tallele carriers and macro- and microalbuminuria (119875 = 001119875 = 002 resp) [91] It was observed that the interaction ofeNOS (G894T polymorphism) andACE (ID alleles) was sig-nificantly associated with more frequent macroalbuminuria(119875 = 0035) [97]
It has also been shown that interaction of eNOS (G894Tpolymorphisms) and MTHFR (C677T and A1298C poly-morphisms) eNOS T1298 C and eNOS T677 T carriershad positive significant association with macroalbuminuriaIn addition significant association of eNOS GT+TT carrierswith lipid profile (119875 lt 005) was shown in this study [99]
C677T andA1298C polymorphisms ofMTHFRwere alsoinvestigated in another study revealing that 677T 1298Cand 677T1298C carriers were significantly associated withmacroalbuminuria (119875 lt 0001) Positive significant asso-ciation when pooling CT+TT genotypes and 677T1298Cwas also found with microalbuminuria (119875 lt 0001) [103]Investigating the interaction of MTHFR (A1298C C677Tpolymorphisms) and ACE (ID alleles) showed a positivesignificant association of ACE D677T (119875 = 0035) and ACED1298C (119875 = 0012) genotypeswithmacroalbuminuria [96]
ACE (ID alleles) polymorphisms were investigated inthree studies In one study positive significant association(119875 lt 001) between DD carriers and progression but notdevelopment of albuminuria was observed [104] In anotherstudy in nephropathic subjects association of DD carriersand T2DM (119875 = 0006) but not nephropathy was revealed[105] However another study did not show significant asso-ciation of ACE with macroalbuminuria [98] Interaction ofACE (ID alleles) with Factor V Leiden (G1691A polymor-phism) was not significant [100]
Association of interleukins including IL-4 and IL-10 withdiabetic nephropathy was also investigated in two studiesStudy of minus592CA polymorphism of IL-10 revealed positivesignificant association between CC carriers and nephropathy(119875 = 0001) [94] and study ofminus590CTpolymorphismof IL-4revealed positive significant association between CT carriersand nephropathy (119875 lt 0001) [101]
Other significant associations between variants and dia-betic nephropathy included AT2R (angiotensin II recep-tor) (minus1332GA polymorphism) VEGF (vascular epitheliumgrowth factor) (+405GC polymorphism) and VDR (TaqIpolymorphism) [92 95 102] ApaI polymorphism of VDRwas not significantly associated with diabetic nephropathy[102]
327 Genes Related to Diabetic Retinopathy All of the 3studies in this subgroup were conducted as case-controlassociation studies [106ndash108]
Investigating nullpositive genotype of GSTM1 in a studywhich used ARMS-PCR for genotyping revealed that nullgenotype is significantly associated with diabetic retinopathy(119875 lt 005) [106] This result was confirmed in another study
by using multiplex PCR as genotyping [107] although nosignificant association between GSTT1 and retinopathy wasfound in this study [107]
Investigating +405GC polymorphism of VEGF alsorevealed positive significant association between GG carriersand diabetic retinopathy (119875 = 0005) [108]
328 Genes Related to Diabetic Foot Ulcer In this subgrouponly one study was found [109] which was case-controldesigned and used ARMS-PCR for genotyping In this studyassociation of minus7CT and minus2578CA polymorphisms ofVEGF with diabetic foot ulcer (DFU) was investigated and apositive significant association betweenAA carriers andDFU(119875 = 003) was observed But no significant association wasfound between minus7CT of VEGF and DFU [109]
4 Discussion
Diabetes mellitus is the eighth most frequent disease leadingcause of death throughout the world and now ranks the fifthfollowing communicable diseases cardiovascular diseasecancer and injuries [110] Prevalence of diabetes mellitus isincreasing worldwide [6]
Type 2 diabetes is the most frequent type of diabetesmellitus [110 111] Multiple genes and environmental factorsaffect the prevalence of T2DM Systematic review and meta-analysis studies have assessed the association between dif-ferent genes and T2DM Glutathione-S-transferase includingGSTMI GSTM1 and GSTP1 are important genes and theirassociation with diabetes has been investigated in two meta-analysis studies [112 113] It was revealed that null genotypeof both GSTM1 and GSTT1 could be as a risk factor fordiabetes while no significant association was found betweenGSTP1 and diabetes [112 113] These results are in linewith our finding and confirming the association of the nullgenotype of GSTT1 and GSTM1 with T2DM in Iranianpopulation [50] The relation between GSTT1 and GSTM1and diabetic retinopathy has also been shown in Iranianpopulation [106 107]
MTHFR is another important gene in association withT2DM and other related complications No associationof C677T polymorphism of MTHFR gene was found inAfricans Asians and Caucasians [114] MTHFR is a genewhich is involved in DNA methylation and synthesis andregulated folate activity It has been reported that mutanthomozygote and heterozygote of C677T polymorphism ofMTHFR increase plasma homocysteine which is an impor-tant factor leading to diabetic nephropathy (DN) and as aresult C677T polymorphism of MTHFR can be associatedwith the development of DN In Caucasians this associationhas also been observed [115] In Iranian population in linewith other populations no significant association was foundbetween MTHFR polymorphisms and T2DM [63] althoughsignificant association of 677T and 1298C alleles with diabeticnephropathy was observed [87] Interaction of two polymor-phisms and also interaction of MTHFR polymorphisms withother genes such as ACE and eNOS showed an associationwith development of DN [96 99]
16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
6 Journal of Diabetes ResearchTa
ble1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Moh
ammadietal2013
[40]
(i)ER120572PvuII(PPPp
pp)
(ii)E
R120572XbaI(XX
Xxxx)
174T2
DM
and174ND
35ndash6
5yrMF
Jahrom
Case
control
PCR-RF
LP
(i)Sign
ificant
associationwith
T2DM
(P=0014)
TC(P
=0007)and
TG(119875=0005)fem
alec
arrie
rs(ii)S
ignificantassociatio
nwith
T2DM
(119875=0002)TC
(119875=0003)andTG
(119875=0009)
femalec
arrie
rs
Motavallianetal2013
[41]
PPAR-1205742Pro12A
la100T2
DM
and100healthy
51yrM
FIsfahan
Case
control
PCR-RF
LP
Negatives
ignificantassociatio
nbetweenAlaA
lacarriers
(119875lt0001)a
ndpo
sitive
significantassociatio
nbetween
AlaPro
carrierswith
T2DM
(119875lt0001)
Sepahi
etal2013
[42]
HNF-1120572Ala98Va
lGLP
-1RTh
r149Met
100T2
DM
and50
healthy
controlsle35
andgt35
yrM
FMashh
adCa
secontrol
PCR-RF
LPNon
significance
Sheikh
haetal2013
[43]
APO
A1M
SP-I
200T2
DM
and200healthy
418yrM
FYazd
Case
control
PCR-RF
LPNon
significance
Yagh
oubietal2013
[44]
CXCL
5minus156GgtC
100T2
DM54y
rand
100healthy
56yrM
FArdabil
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GCcarriers(119875=0006)a
ndnegativ
esignificantassociatio
nof
GGcarrierswith
T2DM
(P=001)
Bahreini
etal2012
[45]
Calpain-10SNP4
3(AG)
102T2
DM
and100healthy
40ndash70y
rM
EastAzerbayjan
Case
control
PCR-RF
LPGallelea
srisk
factor
ofT2
DM
(P=0037)
Derakhshanetal2012
[46]
SDF-1120573G
801A
200T2
DM
and200healthy
40yrM
FRa
fsanjan
Case
control
PCR-RF
LPNon
significance
Haghani
etal2012
[47]
(i)IRS-1G
972R
(ii)IRS
-2G
1057D
336T2
DM
and341h
ealth
y44
ndash63y
rMF
Ilam
andKe
rmanshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
GR(P
=0001)andRR
(119875=00001)carrie
rswith
T2DM
(ii)P
ositive
significant
associationbetweenGDcarriers
andT2
DM
(P=0016)
Alamietal2012
[48]
TCF7L2
rs12
255372
(GT)
236T2
DM
and255healthy
gt37
yrM
FGorgan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersandT2
DM
(P=0014)
Meshk
anietal2012
[49]
(i)ER120572PvuII(PPPp
pp)
(ii)E
R120572XbaI(XX
Xxxx)
155T2
DM
and377controls
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
pooled
Pp+pp
malec
arrie
rs(P
=0001)with
T2DM
(ii)P
ositive
significant
associationof
pooled
XX+
xxmalec
arrie
rs(P
=0026)
with
T2DM
Journal of Diabetes Research 7
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Moasser
etal2012
[50]
GST
M1p
resentnull
GST
T1presentnull
GST
P1Ile105Va
l
171T
2DM
and169healthy
25ndash6
5yrMF
Shira
zCa
secontrol
PCR-RF
LP
GST
M1-n
ull(P=0016)
and
interactionof
GST
M-nullG
STT1-null
(119875=0022)significant
associationwith
T2DM
Moh
addese
tal2012
[51]
SLC3
0A8Arg325Trp
125T2
DM
and125controls
40ndash70y
rMF
Azarbayjan
Case
control
PCR-RF
LPNon
significance
Oladi
etal2012
[52]
Glucokinaseminus30GA
542subjects
18ndash6
5yrMF
Mashh
adCr
osssectio
nal
PCR-RF
LPNon
significance
Palizbanetal2012
[53]
TCF7L2
rs7903146
(CT)
110T2
DM
and80
healthy
46ndash6
7yrMF
Isfahan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersandT2
DM
(P=0008)
Tabatabaei-M
alazyetal2012
[54]
ApoE
E3-E3
E2-E3
E4-E3
156T2
DM
and155healthy
25ndash6
5MF
Tehran
Case
control
PCR-RF
LPNon
significance
Ghasemietal2012
[55]
KCNJ11
E23K
358T2
DM
and388healthy
41ndash6
9yrMF
Rasht
Case
control
Realtim
ePCR
Positives
ignificantassociatio
nbetweenKK
carriersandob
ese
T2DM
(P=0037)
Ranjbare
tal2011[56]
Adipon
ectin
+45TG
minus113
91GA
244T2
DM
and99
healthy
37ndash6
5yrMF
Rafsanjan
Case
control
PCR-RF
LPNon
significant
Mehrab-Moh
seni
etal2011[57]
eNOSVNTR
intro
n4ab
220T2
DM
and96
healthy
53plusmn15yrM
FRa
fsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenaa
orab
carriersand
T2DM
(P=002)
Nosratabadi
etal2011[58]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DM
and100healthy
40yrM
FRa
fsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandT2
DM
(Plt0001)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandT2
DM
Saberietal2011[59]
ENPP
1K121Q
155T2
DM
and377healthy
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LPNon
significance
Fallahetal2010
[60]
SUMO4Met55Va
l(16
3AG
)50
T2DM
and50
healthy
25ndash4
5yrMF
Tehran
Case
control
PCR-RF
LPNon
significance
Heidarietal2010
[61]
UCP
2minus866G
A75
T2DM75NDob
esea
nd75
NDno
nobese35ndash76
yrM
FTehran
Case
control
PCR-RF
LPNon
significance
Nazem
etal2010
[62]
5HTT
LPRSSSLLL
90T2
DM
and90
healthy
54ndash6
6yrMF
Shira
zCa
secontrol
PCR
Non
significance
Bazzaz
etal2010
[63]
MTH
FRC677T
401T
2DM74NDob
esea
nd207
NDno
nobese30ndash
63yrM
FTehran
Case
control
PCR-RF
LPNon
significance
Emam
gholipou
retal2009
[64]
resistin
minus420C
G47
T2DM
and66
healthy
58plusmn9y
rMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandT2
DM
(P=000
9)
Hasani-R
anjbar
etal2009
[65]
CXCL
5minus156G
C230T2
DM
and120healthy
40ndash6
3yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGCor
CCcarriersand
T2DM
(P=000
4)
8 Journal of Diabetes ResearchTa
ble1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
KazemiA
rababadi
etal2009
[66]
IL-4minus590C
TIFN-120574+874T
A160T2
DM
and160healthy
38plusmn9y
rMF
Rafsanjan
Case
control
PCR-RF
LPARM
S-PC
RNon
significance
Arababadi
etal2009
[67]
CCR5
12057532mutation
200T2
DM
and300healthy
40plusmn9y
rMF
Rafsanjan
Case
control
Gap-PCR
Non
significance
Kazemietal2009
[68]
INSR
128T2
DMgt
40yrM
FTehran
Case
control
PCR
CSGE
sequ
encing
Follo
wingmutations
werefou
ndon
lyin
T2DM
511CgtA514Tgt
G586and
628TgtAon
exon
2694GgtCand680GgtAon
exon
31627AgtTon
exon
8ATgtTG
onintro
n9
2007Cgt
CTon
exon
92595Cgt
CTand2669GgtCGon
exon
132706
and2717Cgt
G2752CgtT
2753Cgt
Gonexon
143471Tgt
Aand3516Tgt
Gon
exon
19
Mirz
aeietal2009
[69]
PPAR120574
2Pro12A
la78
norm
al78ob
ese78
T2DM
and78
obeseT
2DM25ndash64
yr
MF
Tehran
Crosssectio
nal
PCR-RF
LPNon
significance
Nikzamiretal2008
[70]
ACEinsertion(I)
deletion(D
)170T2
DM
and144healthyMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(P=002)
Sharifi
etal2008
[71]
HFE
H63D
C282Y
101T
2DM
and101h
ealth
y55plusmn11yrM
FZa
njan
Case
control
PCR
Non
significance
Besharatietal2007
[72]
(i)Ap
oA-IG
-75A
(ii)A
poA-
IC+8
3T215subjects26ndash
64yrM
FTehran
Crosssectio
nal
PCR-RF
LP
(i)Non
significantassociatio
nbetweenG-75A
carriersand
T2DM
(ii)P
ositive
significant
associationbetweenCT
carriers
andT2
DM
(P=0028)
Hasani-R
anjbar
etal2007
[73]
Adipon
ectin
+45TG
80T2
DM
obese72
T2DM
nono
beseand
70healthy
25ndash6
4yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersand
nono
bese
T2DM
(P=004)
Meshk
anietal2007
[74]
PTPN
1minus51delA
minus451AgtGminus467TgtC
minus1023Cgt
Aminus1045GgtAminus1286
3bpdel
ACAminus1291
9bpdel
CTAG
ACTA
A
174T2
DM
and412healthy
23ndash79MF
Tehran
Case
control
PCR
sequ
encing
PCR-RF
LPNon
significance
Meshk
anietal2007
[75]
PPAR120574
Pro12Ala
412T2
DM
and284healthy
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LPNegatives
ignificantassociatio
nbetweenProAlaor
AlaA
lacarriersandT2
DM
(P=0003)
Journal of Diabetes Research 9
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
T2DM
patie
ntsa
ndinsulin
resistance
Nam
varanetal2012
[76]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin
receptor-2+795G
A
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTG
carriersandT2
DM
(P=0032)
(ii)N
onsig
nificantassociatio
nbetween+7
94GA
carriersand
insulin
resistance
Nam
varanetal2011[77]
PPAR120574
Pro12Ala
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
Realtim
ePCR
Positives
ignificantassociatio
nbetweenAlaallelecarriersand
T2DM
(P=0036)
Hossein-nezhadetal2009
[78]
VDRFokI
(FFFfff
)105T2
DM55plusmn10yrM
FTehran
Case
serie
sPC
R-RF
LPPo
sitives
ignificantassociatio
nbetweenffcarriersandinsulin
resistanceind
ex(P
=002)
Moo
sapo
oretal2007
[79]
PTPN
1148insG
71T2
DM
and264ND
20ndash80y
rMF
Tehran
Case
control
PCR-RF
LP
Negatives
ignificantassociatio
nbetween148insGcarriersand
insulin
resistanceind
ex(119875=0041)
T2DM
patie
ntsa
ndheartd
iseases
Bayatm
akoo
etal2013
[80]
Paraoxon
ase116
3TA
(L55M)
105CA
DD
Mand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPNon
significance
Bayatm
akoo
etal2012
[81]
Paraoxon
ase1575Ggt
A(Q
192R
)105DMCADand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenRR
carriersand
CADD
M(Plt005)
Estegh
amatietal2012
[82]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin+276G
T114
CADD
Mand127DM
42ndash71yrMF
Tehran
Case
control
PCR-RF
LP
(i)Negatives
ignificant
associationbetween45TT
carriersandCA
D(P
=0033)
(ii)P
ositive
significant
associationbetween276G
GcarriersandCA
D(P
=0023)
Rahimietal2012
[83]
eNOSG8
94T
CETP
B1
102CA
DD
M105
CADN
D101
DMand
92ND45ndash66
yrM
FKe
rmanshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
concom
itant
presence
ofNOS3
TalleleandCE
PTB1
allelewith
T2DM
(P=000
4)andCA
D(119875=0002)
Assalietal2011[84]
AT1RA116
6C145CA
DD
Mand164CA
D
lt50
andge50
yrM
FMashh
adCa
secontrol
PCR-RF
LPPo
sitives
ignificantassociatio
nof
ACandCC
carrierswith
DM
(119875=001)
Emam
gholipou
retal2009
[85]
Resistin
minus420C
G113CA
Dwith
andwith
outD
M
58plusmn9yrM
FTehran
Crosssectio
nal
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDM
(119875=0009)
10 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Fallahetal2010
[86]
MMP-3minus1612
5A6A
305CA
DD
Mand313DM
61plusmn9yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetween6A
6AcarriersandCA
S(P
=0008)
Vaisi-Raygani
etal2010
[87]
BChE
KG1
615A
APO
EE2
E3E4
118DM162
CADN
D172
DMCADand
179healthy
42ndash6
8yrMF
Kerm
anshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GAA
Aand
E4carrierswith
CADandDM
(Plt005)
Positives
ignificantassociatio
nof
BChE
KAp
oE4carrierswith
CADand
DM
(Plt005)
Sign
ificant
associationof
BChE
KAp
oE4with
lipid
profi
le(119875lt005)
Rahimietal2009
[88]
Factor
VLeidenG
1691A
Prothrom
binG2
0210A
MTH
FRC677T
65CA
DD
M52CA
DN
Dand
59healthy46
064y
rMF
Kerm
anshah
Case
control
PCR-RF
LPNon
significance
Nakhjavanietal2007
[89]
ACEID
82DM
with
hypertensio
nand87
DM
with
outh
ypertension
49ndash6
3yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
hypertensio
n(P
=0026)
Vaisi-Raygani
etal2007
[90]
Apolipop
roteinE2E3
E4
152CA
DD
M262
CADN
D
and300healthy35ndash73y
rMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nof
E2andE4
allelec
arrie
rswith
CAD(Plt0001)
T2DM
patie
ntsa
ndneph
ropathy
Rahimietal2013
[91]
eNOS4abG
894T
63T2
DMm
icroalbu
minuria
57T2
DMm
acroalbu
minuria
52T2
DMnormoalbum
inuria
121D
Nand
101h
ealth
y45ndash6
6yrMF
Kerm
anshah
Case
control
PCR
PCR-RF
LP
Positives
ignificantassociatio
nof
4aor
894T
allelecarriersand
macro-(P=001)o
rmicroalbu
minuria(P
=002)
Rahimietal2013
[92]
AT2R
minus1332GA
28T2
DMm
icroalbu
minuria
22T2
DMm
acroalbu
minuria
20T2
DMnormoalbum
inuria
and112healthy43ndash6
3yrMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(P
=0016)
Shahsavare
tal2013
[93]
SUMO4163A
G(M
55V)
50T2
DD
Nand50
T2DM
non-DN25ndash45
yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(Plt005)
Arababadi
etal2012
[94]
IL-10minus592C
A100T2
DMnon
-DN100
T2DMD
Nand100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDN
(119875=0001)
Journal of Diabetes Research 11
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2012
[95]
VEG
F+4
05G
C255T2
DMm
icroalbu
minuria
and235T2
DMnon
albu
minuric
50ndash6
7yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersand
albu
minuria(P
=0002)
Rahimietal2012
[96]
MTH
FRA1298C
C677T
ACEID
72T2
DMM
icAlb
68T2
DMM
acAlband72
T2DMnon
-DN46ndash
65yrM
FKe
rmanshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nof
ACED677T(P
=0035)
and
ACED12
98C(P
=0012)
carrierswith
macroalbu
minuria
Rahimietal2012
[97]
eNOSG8
94T
ACEID
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nbetweenAC
EDcarriersand
macroalbu
minuria(P
=0035)
Feleh
garietal2011[98]
ACEID
68T2
DMm
acroalbu
minuria
and72
T2Dmnormoalbum
inuria
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR
Non
significance
Jafarietal2011[99]
eNOSG8
94T
MTH
FRC677TA
1298C
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
eNOST1298
CandeN
OS
T677Tcarrierswith
macroalbu
minuria(Plt005)
(ii)S
ignificantassociatio
nof
eNOSGT+
TTcarrierswith
lipid
profi
le(Plt005)
Rahimietal2011[100]
ACEID
Factor
VLeidenG
1691A
217mean55both
Kerm
anshah
Case
control
PCR
PCR-RF
LPNon
significance
Arababadi2010[101]
IL-4minus590C
T100T2
DMD
Nand150healthy
33ndash4
7yrMF
Rafsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenCT
carriersandDN
(119875lt0001)
Nosratabadi
etal2010
[102]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DMnon
-DN100
T2DMD
Nand
100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandDN
(119875=0012)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandDN
Rahimietal2010
[103]
MTH
FRC677TA
1298C
72T2
DMm
icrolbum
iunira
68T2
DMm
acroalbu
minuria
and72
T2DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
677T1298C
and677T
1298C
carrierswith
macroalbu
minoria
(Plt0001)
(ii)P
ositive
significant
associationof
CT+T
Tand
677T
1298Ccarrierswith
microalbu
minuria(Plt0001)
12 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2009
[104]
ACEID
129T
2DMm
icrolbum
iunira
48T2
DMm
acroalbu
minuria
and145T
2DMnormoalbum
inuria
594plusmn85y
rMF
Tehran
Crosssectio
nal
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
progressionof
albu
minuria
(119875lt001)b
utno
tits
developm
ent
Nikzamiretal2006
[105]
ACEID
85T2
DMD
N85T2
DMnon
-DN
and91
healthy37ndash6
7yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(119875=0006)b
utno
tDN
T2DM
patie
ntsa
ndretin
opathy
Abbasietal2013
[106]
GST
M1n
ullp
ositive
80DRand80
healthy
30ndash70y
rMF
Rasht
Case
control
ARM
S-PC
RNullgenotypes
ignificant
association
Plt005
Dadbinp
oure
tal2013
[107]
(i)GST
M1n
ullp
ositive
(ii)G
STT1nullp
ositive
57DRand58
non-DR
35ndash6
5yrMF
Yazd
Case
control
Multip
lexPC
R
(i)Nullgenotypeo
fGST
M1o
rGST
T1sig
nificantassociatio
n(119875=004)
(ii)N
onsig
nificantassociatio
nof
GST
T1nu
llcarrierswith
DR
Fegh
hietal2011[108]
VEG
F+4
05G
C119
diabeticsw
ithPD
Rand279
diabeticsw
ithNPD
R47ndash6
6yrMF
Ahvaz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersanddiabetic
retin
opathy
(P=0005)
T2DM
patie
ntsa
ndfoot
ulcer
Amolietal2011[109]
(i)VEG
Fminus7C
T(ii)V
EGFminus2578CA
247T2
DM
with
DFU
241
T2DM
with
outD
FUand
98healthy
43ndash6
4MF
Tehran
Case
control
ARM
S-PC
R
(i)Non
significantassociatio
nof
minus7C
Tcarrierswith
DFU
(ii)P
ositive
significant
associationbetweenAAcarriers
andDFU
(P=003)
SNPsin
glenu
cleotid
epo
lymorph
ismT
1DMtype1d
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4T2
DMtype2diabetes
mellitusP
CRp
olym
erasechainreactio
nRF
LPrestrictio
nfragmentlengthpo
lymorph
ismILinterle
ukinSS-PC
Rsequ
ence
specificP
CRV
DR
vitamin
DreceptorT
AP2
transpo
rter
2AT
P-bind
ingcassetteA
RMS-PC
Ram
plificatio
nrefractory
mutationsyste
mPC
RPC
R-SSPPC
Rsin
glespecificprim
erT
GF120573
transform
inggrow
thfactor120573D
Md
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4
MODY
maturity
onsetd
iabeteso
fthe
youn
gHNF-
1120572h
epatocytenu
clear
factor
1120572M
VCm
icrovascular
complicationsT
CF7L
2transcrip
tionfactor
7-lik
e2PC
R-SSCA
PCR
singlestr
andconformationpo
lymorph
ismanalysis
ER120572estr
ogen
receptor120572N
D
nond
iabeticsTC
totalcholesterolTG
trig
lycerid
esP
PAR-1205742peroxisomep
roliferator-activates
receptor120574G
LP-1R
glucagon
-like
peptid
1receptorAPO
apo
lipop
roteinC
XCL5chemokineC
-X-C
motifligand
5SD
F-1120573stro
malderiv
edfactor-1120573IRS
1amp2insulin
receptor
substrate1amp
2GSTglutathione-S-tr
ansfe
raseSLC
30A8solublecarrier3
0A8KC
NJPo
tassium
inwardly-rectify
ingchanneleN
OSendo
thelial
nitricoxidesynthaseVNTR
variablen
umbero
ftandem
repeatsEN
PP1ectoenzymen
ucleotidep
yrop
hosphateph
osph
odieste
rase1SU
MOsmallubiqu
itin-lik
emod
ifier4UCP
2un
coup
lingp
rotein
2MTH
FR
methylenetetrahydrofolateredu
ctaseIFN120574interferon120574C
CR5C-
Cchem
okiner
eceptortype5
INSR
insulin
receptorC
SGE
conformation-sensitive
gelelectroph
oresis
ACE
angiotensin
Icon
vertingenzyme
HFE
hem
ochrom
atosisgenePTP
N1proteintyrosin
Phosph
atase1B
CADcoron
arya
rteryd
iseaseCE
TPcho
leste
ryleste
rtransferp
roteinA
T1R
angiotensin
IreceptorMMP3
matrix
metalloproteinase
3CA
Scoronary
artery
steno
sisB
ChEK
Butyrylcho
linesteraseK
DNdiabetic
neph
ropathyAT
2Rang
iotensin
IIreceptorV
EGFvascularepith
elium
grow
thfactorD
Rdiabeticretin
opathy
PDR
proliferativ
ediabetic
retin
opathy
NPD
Rno
n-PD
RDFU
diabetic
foot
ulcer
Journal of Diabetes Research 13
321 T1DM Related Genes All the studies in this subgroupincluding 12 studies [22ndash33] were in a case control studydesign using PCR (polymerase chain reaction) [33] PCR-RFLP (restriction fragment length polymorphism) [22 2325 26 32] PCR-SSP (single specific primer) [24 28ndash32]and ARMS-PCR (amplification refractory mutation systemPCR) [27] method In all studies both men and women wereincluded and the overall 2519 subjects were under 40 yearsold
Association of interleukins including IL-18 (interleukin)and IL-12 with T1DM revealed that the minus137CG polymor-phism of IL-18 had significant association with T1DM (119875 =0037 119875 = 00001) while no significant relation was observedbetween minus607AC variant of this gene and T1DM [24 28]Investigating IL-12 also showed that there was a significantassociation between +1188AC polymorphism of this geneand T1DM (119875 = 0035) [30]
In 2 studies the association of +49AG variant of CTLA-4 (cytotoxic T lymphocyte associated antigen 4) was investi-gated and it was revealed that there was a positive significantassociation between AG genotype and T1DM (119875 = 001 119875 lt0001) [22 32] One of these studies also revealed that therewas a negative relation betweenAA genotype and T1DM [32]
Vitamin D receptor (VDR) was investigated in 2 studies[25 26] Both of them assessed the association of FokI BsmIApaI and TaqI variants of VDR with T1DM In one studywhichwas performed on 114 subjects Aa (119875 = 0003) FF (119875 =0008) and Bb (119875 = 0014) genotypes were shown to be pos-itively associated with T1DM but no significant associationwas observed between TaqI polymorphism and T1DM [25]Another study which was performed on 187 subjects showedno significant association between T1DM and FokI BsmIand ApaI However TT genotype was observed to be morefrequent in controls (119875 = 0007) and negatively associatedwith T1DM [26]
Different polymorphisms of TAP2 and their associationwith T1DM were investigated in 191 subjects It was shownthat Ile379Val and Stop687Gln had significant associationwith T1DM (119875 = 0001 and 119875 = 0013 resp) Other variantsof TAP2 (transporter 2 ATP-binding cassette) includingAla565Thr Arg651Cys and Ala665Thr were not associatedwith T1DM significantly [27]
Association of alleles A2ndashA9 of CD4 with T1DM wasassessed in 200 subjects It was revealed that A3 allele hadnegative (119875 = 0025) and A5 had positive (119875 = 0001)significant association with T1DM [33]
Association of some other genes including osteopontin(rs1126772 polymorphism) integrin 1205724 (rs1449263 polymor-phism) CD44 (rs8193 polymorphism) and TGF120573 (trans-forming growth factor) (+915CG polymorphism) was alsoinvestigated in 2 studies and no significant relation wasobserved between these variants and T1DM [23 29]
322 MODY In this category only one study was found [34]and the association of Val255Met polymorphism of HNF120572and diabetes was investigated in 101 subjects includingMODY subjects their relatives and healthy controls [34]Thestudy was designed as a case control association study andPCR-RFLP and direct sequencing was used for genotyping
of variants Val255Met mutation in this investigation wasobserved in MODY subjects and their relatives but not incontrol group
323 T2DM Related Genes In this subgroup 42 studieswere assessed and all of them were designed as case controlassociation studies [22 35ndash68 70ndash75] except for one whichwas cross sectionally designed [69] In 33 studies PCR- RFLPwas used for genotyping [22 36ndash38 40ndash54 56 58ndash61 63ndash66 69 72ndash75] In 5 of them PCR was used [35 57 62 70 71]and the remaining studies PCR-SCA [39] real-timePCR [55]ARMS-PCR [66] Gap PCR [67] and CSGE (conformation-sensitive gel electrophoresis) sequencing [68] as the genotyp-ing method were applied
Association between two polymorphisms of TCF7L2including rs7903146 (CT) and rs12255372 (GT)was assessedin three studies [38 48 53] In one study investigatingrs7903146 (CT) in 466 subjects significant difference in thefrequency of CC and CT genotypes was observed betweenT2DM and control group (119875 = 0045) [38] However inanother study this polymorphism showed a positive signifi-cant associationwith TT genotype in T2DM (119875 = 0008) [53]Investigation of rs12255372 (GT) polymorphism of TCF7L2in another study showed that among 491 subjects there wasa positive significant association between TT carriers andT2DM (119875 = 0014) [48]
Investigating the association of calreticulinwith T2DM in650 subjects showed two mutations only in case group 9 bpdeletion of 397ndash399 codons and GgtT mutation at IVSII-142[39]
Association of estrogen receptor 120572 and its PvuII(PPPppp) and XbaI(XXXxxx) polymorphism with T2DM intwo studies was assessed [40 49] In one study the significantassociation of PvuII and XbaI polymorphisms with T2DMwas observed (119875 = 0014 and 119875 = 0002 resp) [40] Inanother study it was revealed that pooled Pp+pp and XX+xxmale carriers have positive significant associationwithT2DM(119875 = 0001 and 119875 = 0026 resp) [49]
Association of Pro12Ala polymorphism of PPAR120574 withT2DMwas investigated in three studies [41 69 75] Negativesignificant association of AlaAla genotype with T2DM wasobserved in two studies (119875 = 0003) [41 75] AlaPro carrierswere shown to be positively associated in one study [41] andnegatively associated in another study [75] with T2DM (119875 lt0001 and 119875 = 0003 resp) However in the third studyno significant association was observed between Pro12Alapolymorphism of PPAR120574 and T2DM [69]
Association of different polymorphisms of ApoAI withT2DM was investigated in two studies [43 72] In one studyinvestigation of MSPI polymorphism showed no significantassociation with T2DM [43] In another study it was shownthat G-75A polymorphism of ApoAI was not associated withT2DM while a significant association was found betweenC+83T polymorphism and T2DM (119875 = 0028) [72]
Two studies assessed the association of minus156GgtC poly-morphism of CXCL5 with T2DM [44 65] In one studypositive significant association of GC carriers (119875 = 0006)and negative association of GG carriers (119875 = 001) was foundbetween diabetic patients and healthy controls [44] and
14 Journal of Diabetes Research
in another study positive significant association was foundbetween GC or CC carriers and T2DM (119875 = 0009) [64]
Adiponectin and its association with T2DM were inves-tigated in two studies [56 73] In one study two variantsincluding +45TG and minus11391GA were investigated but nosignificant relation was found between these two polymor-phisms and T2DM [56] However in another study investi-gating +45TG polymorphism of adiponectin it was revealedthat nonobese T2DM subjects had significantly higher TTgenotype (119875 = 004) [73]
In one study that investigated insulin receptor gene thefollowing mutations were found only in T2DM 511CgtA514TgtG 586 and 628TgtA on exon 2 694GgtC 680GgtA onexon 3 1627AgtT on exon 8 ATgtTG on intron 9 2007CgtCTon exon 9 2595CgtCT and 2669GgtCG on exon 13 2706 and2717CgtG 2752CgtT and 2753CgtG on exon 14 and 3471TgtAand 3516TgtG on exon 19 These mutations were not seen incontrol subjects [68]
Other variants which had significant association withT2DM included haptoglobin (allele 2-2) leptin (G-2548Apolymorphism) paraoxonase 2 (Ser311Cys polymorphism)GST (glutathione-S-transferase) M1 and GSTM1GSTT1interaction calpain-10 (SNP (single nucleotide polymor-phism) 43) IRS-1 (G972R polymorphism) and IRS-2(G1057D polymorphism) VDR (vitamin D receptor) (TaqIpolymorphism) KCNJ11 (E23K polymorphism) eNOS(endothelial nitric oxide synthase) VNTR (intron 4 ab pol-ymorphism) resistin (minus420CG polymorphism) and ACE(InsertionDeletion) [35ndash37 45 47 50 55 57 58 64 70]
In contrast to above variants CTLA4 (+49AG poly-morphism) HNF-1120572 (Ala98Val polymorphism) GLP-1R(glucagon-like peptid 1 receptor) (Thr149Met polymor-ohism) SLC30A8 (Arg325Trp polymorphism) GSTP1(Ile105Val polymorphism) glucokinase (minus30GA polymor-phism) SDF-1120573 (stromal derived factor -1 120573) (G801A poly-morphism) ApoE (apolipoprotein E) ENPP1 (ectoenzymenucleotide pyrophosphate phosphodiesterase 1) (K121Q poly-morphism) SUMO4 (small ubiquitin-like modifier 4)Met55Val polymorphism) MTHFR (C677T polymorphism)UCP2 (uncoupling protein 2) (minus866GA polymorphism)5HTTLPR IL-4 (minus590CT polymorphism) IFN-120574 (inter-feron 120574) (+874TA polymorphism) CCR5 (C-C chemokinereceptor type 5) (12057532mutation) HFE (hemochromatosisgene) (H63D C282Y PTPN1 (protein tyrosin Phosphatase1B)minus51delA minus451AgtG minus467TgtC minus1023CgtA minus1045GgtAminus1286 3 bp del ACA minus1291 9 bp del CTAGACTAA poly-morphisms) were not significantly associated with T2DM[22 42 46 50ndash52 54 59ndash63 66 67 71 74]
324 Genes Related to Insulin Resistance In this subgroupfour studies were assessed and all were designed as case-control association studies Three studies used PCR-RFL [7678 79] and one study used real-time PCR [77] for genotyping
The studies assessed in this subgroup showed a positiveassociation of TG carriers of +45TG polymorphism ofadiponectin (119875 = 0032) and Ala allele carriers of Pro12Alapolymorphism of PPAR120574 (119875 = 0036) with T2DM [76 77]A positive significant association of ff carriers of VDR wasalso shown (FokI polymorphism) (119875 = 002) and negative
association of 148insG carriers of PTPN1 (148insG polymor-phism) (119875 = 0041) with insulin resistance index [7879] However no significant association was shown betweenadiponectin receptor-2+795GA and T2DM [76]
325 Genes Related to Cardiovascular Disease in DiabetesDesign of all 11 studies in this subgroup was case-controlassociation study [80ndash84 86ndash90] except one study which wasdesigned as cross sectional [85] PCR-RFLP was used in all ofthem for genotyping [80ndash88 90] except in one study whichused ARMS-PCR method [89]
Paraoxonase 1 (163TA polymorphism) was the only vari-ant in this subgroup which was not significantly associatedwith atherosclerosis risk in T2DM [80] Investigation ofanother polymorphism of Paraoxonase 1 (Q192R) revealedthat diabetics with CAD had significant increase in RRgenotype (119875 lt 005) [81]
Investigating B1 and B2 alleles of CETP TaqI B allele in400 subjects showed that pooling of B1B1+B1B2 and B1B1genotypes had significant association with T2DM and CAD(119875 lt 001) On the other hand assessing the G894T poly-morphism of eNOS showed positive significant associationbetween TG and TT carriers and CAD (119875 lt 005) It was alsoshown that concomitant presence of NOS3 T allele and CEPTB1 allele was significantly associated with T2DM (119875 = 0004)and CAD (119875 = 0002) [83]
Investigation of apolipoprotein E (E2 E3 and E4) allelesshowed the association of E2 and E4 alleles with CAD(119875 lt 0001) [84 87] Also it was shown that interactionof butyrylcholinesterase (BChE K) and apolipoprotein E(ApoE) was associated significantly with CAD and diabetesApoE4BChE K had significant association with lipid profilesas well (119875 lt 005) [87]
Adiponectin +276GT and +45TG were significantlyassociated with CAD (119875 = 0023 and 0033 resp) [82] whileinvestigating minus1612 5A6A polymorphism of MMP-3 (matrixmetalloproteinase 3) showed a significant association withCAS (coronary artery stenosis) (119875 = 0008) [86]
In addition A1166C polymorphism of AT1R (angiotensinI receptor) and minus420CG polymorphism of resistin in dia-betic patients with CAD revealed significant association withdiabetes 119875 = 001 and 119875 = 0009 respectively [84 85]
Another study showed insertion(I)deletion(D) polymor-phismof angiotensin converting enzyme (ACE)DDgenotypewas significantly associated with higher blood pressure (119875 =0026) [89]
Factor V Leiden (G1691A polymorphism) prothrombin(G20210A polymorphism) and MTHFR (methylenetetrahy-drofolate reductase) (C677T polymorphism) were the vari-ants which were not significantly associated with CAD andT2DM in this subgroup [88]
326 Genes Related to Diabetic Nephropathy All of 15 studiesin this subgroup were designed as case-control associationstudies [91ndash106] In 7 studies PCR-RFLP was used forgenotyping [92ndash95 99 102 103] in four studies PCRwas used[98 101 104 105] and in 4 of them both PCR and PCR-RFLPwere used [91 96 97 100]
Journal of Diabetes Research 15
Studying the association of 163AG polymorphism ofSUMO4 showed a positive significant association betweenAA carriers and diabetic nephropathy (119875 lt 005) [93]
Studying the interaction of eNOS4ab and G894Trevealed positive significant association between 4a or 894Tallele carriers and macro- and microalbuminuria (119875 = 001119875 = 002 resp) [91] It was observed that the interaction ofeNOS (G894T polymorphism) andACE (ID alleles) was sig-nificantly associated with more frequent macroalbuminuria(119875 = 0035) [97]
It has also been shown that interaction of eNOS (G894Tpolymorphisms) and MTHFR (C677T and A1298C poly-morphisms) eNOS T1298 C and eNOS T677 T carriershad positive significant association with macroalbuminuriaIn addition significant association of eNOS GT+TT carrierswith lipid profile (119875 lt 005) was shown in this study [99]
C677T andA1298C polymorphisms ofMTHFRwere alsoinvestigated in another study revealing that 677T 1298Cand 677T1298C carriers were significantly associated withmacroalbuminuria (119875 lt 0001) Positive significant asso-ciation when pooling CT+TT genotypes and 677T1298Cwas also found with microalbuminuria (119875 lt 0001) [103]Investigating the interaction of MTHFR (A1298C C677Tpolymorphisms) and ACE (ID alleles) showed a positivesignificant association of ACE D677T (119875 = 0035) and ACED1298C (119875 = 0012) genotypeswithmacroalbuminuria [96]
ACE (ID alleles) polymorphisms were investigated inthree studies In one study positive significant association(119875 lt 001) between DD carriers and progression but notdevelopment of albuminuria was observed [104] In anotherstudy in nephropathic subjects association of DD carriersand T2DM (119875 = 0006) but not nephropathy was revealed[105] However another study did not show significant asso-ciation of ACE with macroalbuminuria [98] Interaction ofACE (ID alleles) with Factor V Leiden (G1691A polymor-phism) was not significant [100]
Association of interleukins including IL-4 and IL-10 withdiabetic nephropathy was also investigated in two studiesStudy of minus592CA polymorphism of IL-10 revealed positivesignificant association between CC carriers and nephropathy(119875 = 0001) [94] and study ofminus590CTpolymorphismof IL-4revealed positive significant association between CT carriersand nephropathy (119875 lt 0001) [101]
Other significant associations between variants and dia-betic nephropathy included AT2R (angiotensin II recep-tor) (minus1332GA polymorphism) VEGF (vascular epitheliumgrowth factor) (+405GC polymorphism) and VDR (TaqIpolymorphism) [92 95 102] ApaI polymorphism of VDRwas not significantly associated with diabetic nephropathy[102]
327 Genes Related to Diabetic Retinopathy All of the 3studies in this subgroup were conducted as case-controlassociation studies [106ndash108]
Investigating nullpositive genotype of GSTM1 in a studywhich used ARMS-PCR for genotyping revealed that nullgenotype is significantly associated with diabetic retinopathy(119875 lt 005) [106] This result was confirmed in another study
by using multiplex PCR as genotyping [107] although nosignificant association between GSTT1 and retinopathy wasfound in this study [107]
Investigating +405GC polymorphism of VEGF alsorevealed positive significant association between GG carriersand diabetic retinopathy (119875 = 0005) [108]
328 Genes Related to Diabetic Foot Ulcer In this subgrouponly one study was found [109] which was case-controldesigned and used ARMS-PCR for genotyping In this studyassociation of minus7CT and minus2578CA polymorphisms ofVEGF with diabetic foot ulcer (DFU) was investigated and apositive significant association betweenAA carriers andDFU(119875 = 003) was observed But no significant association wasfound between minus7CT of VEGF and DFU [109]
4 Discussion
Diabetes mellitus is the eighth most frequent disease leadingcause of death throughout the world and now ranks the fifthfollowing communicable diseases cardiovascular diseasecancer and injuries [110] Prevalence of diabetes mellitus isincreasing worldwide [6]
Type 2 diabetes is the most frequent type of diabetesmellitus [110 111] Multiple genes and environmental factorsaffect the prevalence of T2DM Systematic review and meta-analysis studies have assessed the association between dif-ferent genes and T2DM Glutathione-S-transferase includingGSTMI GSTM1 and GSTP1 are important genes and theirassociation with diabetes has been investigated in two meta-analysis studies [112 113] It was revealed that null genotypeof both GSTM1 and GSTT1 could be as a risk factor fordiabetes while no significant association was found betweenGSTP1 and diabetes [112 113] These results are in linewith our finding and confirming the association of the nullgenotype of GSTT1 and GSTM1 with T2DM in Iranianpopulation [50] The relation between GSTT1 and GSTM1and diabetic retinopathy has also been shown in Iranianpopulation [106 107]
MTHFR is another important gene in association withT2DM and other related complications No associationof C677T polymorphism of MTHFR gene was found inAfricans Asians and Caucasians [114] MTHFR is a genewhich is involved in DNA methylation and synthesis andregulated folate activity It has been reported that mutanthomozygote and heterozygote of C677T polymorphism ofMTHFR increase plasma homocysteine which is an impor-tant factor leading to diabetic nephropathy (DN) and as aresult C677T polymorphism of MTHFR can be associatedwith the development of DN In Caucasians this associationhas also been observed [115] In Iranian population in linewith other populations no significant association was foundbetween MTHFR polymorphisms and T2DM [63] althoughsignificant association of 677T and 1298C alleles with diabeticnephropathy was observed [87] Interaction of two polymor-phisms and also interaction of MTHFR polymorphisms withother genes such as ACE and eNOS showed an associationwith development of DN [96 99]
16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Journal of Diabetes Research 7
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Moasser
etal2012
[50]
GST
M1p
resentnull
GST
T1presentnull
GST
P1Ile105Va
l
171T
2DM
and169healthy
25ndash6
5yrMF
Shira
zCa
secontrol
PCR-RF
LP
GST
M1-n
ull(P=0016)
and
interactionof
GST
M-nullG
STT1-null
(119875=0022)significant
associationwith
T2DM
Moh
addese
tal2012
[51]
SLC3
0A8Arg325Trp
125T2
DM
and125controls
40ndash70y
rMF
Azarbayjan
Case
control
PCR-RF
LPNon
significance
Oladi
etal2012
[52]
Glucokinaseminus30GA
542subjects
18ndash6
5yrMF
Mashh
adCr
osssectio
nal
PCR-RF
LPNon
significance
Palizbanetal2012
[53]
TCF7L2
rs7903146
(CT)
110T2
DM
and80
healthy
46ndash6
7yrMF
Isfahan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersandT2
DM
(P=0008)
Tabatabaei-M
alazyetal2012
[54]
ApoE
E3-E3
E2-E3
E4-E3
156T2
DM
and155healthy
25ndash6
5MF
Tehran
Case
control
PCR-RF
LPNon
significance
Ghasemietal2012
[55]
KCNJ11
E23K
358T2
DM
and388healthy
41ndash6
9yrMF
Rasht
Case
control
Realtim
ePCR
Positives
ignificantassociatio
nbetweenKK
carriersandob
ese
T2DM
(P=0037)
Ranjbare
tal2011[56]
Adipon
ectin
+45TG
minus113
91GA
244T2
DM
and99
healthy
37ndash6
5yrMF
Rafsanjan
Case
control
PCR-RF
LPNon
significant
Mehrab-Moh
seni
etal2011[57]
eNOSVNTR
intro
n4ab
220T2
DM
and96
healthy
53plusmn15yrM
FRa
fsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenaa
orab
carriersand
T2DM
(P=002)
Nosratabadi
etal2011[58]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DM
and100healthy
40yrM
FRa
fsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandT2
DM
(Plt0001)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandT2
DM
Saberietal2011[59]
ENPP
1K121Q
155T2
DM
and377healthy
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LPNon
significance
Fallahetal2010
[60]
SUMO4Met55Va
l(16
3AG
)50
T2DM
and50
healthy
25ndash4
5yrMF
Tehran
Case
control
PCR-RF
LPNon
significance
Heidarietal2010
[61]
UCP
2minus866G
A75
T2DM75NDob
esea
nd75
NDno
nobese35ndash76
yrM
FTehran
Case
control
PCR-RF
LPNon
significance
Nazem
etal2010
[62]
5HTT
LPRSSSLLL
90T2
DM
and90
healthy
54ndash6
6yrMF
Shira
zCa
secontrol
PCR
Non
significance
Bazzaz
etal2010
[63]
MTH
FRC677T
401T
2DM74NDob
esea
nd207
NDno
nobese30ndash
63yrM
FTehran
Case
control
PCR-RF
LPNon
significance
Emam
gholipou
retal2009
[64]
resistin
minus420C
G47
T2DM
and66
healthy
58plusmn9y
rMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandT2
DM
(P=000
9)
Hasani-R
anjbar
etal2009
[65]
CXCL
5minus156G
C230T2
DM
and120healthy
40ndash6
3yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGCor
CCcarriersand
T2DM
(P=000
4)
8 Journal of Diabetes ResearchTa
ble1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
KazemiA
rababadi
etal2009
[66]
IL-4minus590C
TIFN-120574+874T
A160T2
DM
and160healthy
38plusmn9y
rMF
Rafsanjan
Case
control
PCR-RF
LPARM
S-PC
RNon
significance
Arababadi
etal2009
[67]
CCR5
12057532mutation
200T2
DM
and300healthy
40plusmn9y
rMF
Rafsanjan
Case
control
Gap-PCR
Non
significance
Kazemietal2009
[68]
INSR
128T2
DMgt
40yrM
FTehran
Case
control
PCR
CSGE
sequ
encing
Follo
wingmutations
werefou
ndon
lyin
T2DM
511CgtA514Tgt
G586and
628TgtAon
exon
2694GgtCand680GgtAon
exon
31627AgtTon
exon
8ATgtTG
onintro
n9
2007Cgt
CTon
exon
92595Cgt
CTand2669GgtCGon
exon
132706
and2717Cgt
G2752CgtT
2753Cgt
Gonexon
143471Tgt
Aand3516Tgt
Gon
exon
19
Mirz
aeietal2009
[69]
PPAR120574
2Pro12A
la78
norm
al78ob
ese78
T2DM
and78
obeseT
2DM25ndash64
yr
MF
Tehran
Crosssectio
nal
PCR-RF
LPNon
significance
Nikzamiretal2008
[70]
ACEinsertion(I)
deletion(D
)170T2
DM
and144healthyMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(P=002)
Sharifi
etal2008
[71]
HFE
H63D
C282Y
101T
2DM
and101h
ealth
y55plusmn11yrM
FZa
njan
Case
control
PCR
Non
significance
Besharatietal2007
[72]
(i)Ap
oA-IG
-75A
(ii)A
poA-
IC+8
3T215subjects26ndash
64yrM
FTehran
Crosssectio
nal
PCR-RF
LP
(i)Non
significantassociatio
nbetweenG-75A
carriersand
T2DM
(ii)P
ositive
significant
associationbetweenCT
carriers
andT2
DM
(P=0028)
Hasani-R
anjbar
etal2007
[73]
Adipon
ectin
+45TG
80T2
DM
obese72
T2DM
nono
beseand
70healthy
25ndash6
4yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersand
nono
bese
T2DM
(P=004)
Meshk
anietal2007
[74]
PTPN
1minus51delA
minus451AgtGminus467TgtC
minus1023Cgt
Aminus1045GgtAminus1286
3bpdel
ACAminus1291
9bpdel
CTAG
ACTA
A
174T2
DM
and412healthy
23ndash79MF
Tehran
Case
control
PCR
sequ
encing
PCR-RF
LPNon
significance
Meshk
anietal2007
[75]
PPAR120574
Pro12Ala
412T2
DM
and284healthy
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LPNegatives
ignificantassociatio
nbetweenProAlaor
AlaA
lacarriersandT2
DM
(P=0003)
Journal of Diabetes Research 9
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
T2DM
patie
ntsa
ndinsulin
resistance
Nam
varanetal2012
[76]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin
receptor-2+795G
A
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTG
carriersandT2
DM
(P=0032)
(ii)N
onsig
nificantassociatio
nbetween+7
94GA
carriersand
insulin
resistance
Nam
varanetal2011[77]
PPAR120574
Pro12Ala
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
Realtim
ePCR
Positives
ignificantassociatio
nbetweenAlaallelecarriersand
T2DM
(P=0036)
Hossein-nezhadetal2009
[78]
VDRFokI
(FFFfff
)105T2
DM55plusmn10yrM
FTehran
Case
serie
sPC
R-RF
LPPo
sitives
ignificantassociatio
nbetweenffcarriersandinsulin
resistanceind
ex(P
=002)
Moo
sapo
oretal2007
[79]
PTPN
1148insG
71T2
DM
and264ND
20ndash80y
rMF
Tehran
Case
control
PCR-RF
LP
Negatives
ignificantassociatio
nbetween148insGcarriersand
insulin
resistanceind
ex(119875=0041)
T2DM
patie
ntsa
ndheartd
iseases
Bayatm
akoo
etal2013
[80]
Paraoxon
ase116
3TA
(L55M)
105CA
DD
Mand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPNon
significance
Bayatm
akoo
etal2012
[81]
Paraoxon
ase1575Ggt
A(Q
192R
)105DMCADand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenRR
carriersand
CADD
M(Plt005)
Estegh
amatietal2012
[82]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin+276G
T114
CADD
Mand127DM
42ndash71yrMF
Tehran
Case
control
PCR-RF
LP
(i)Negatives
ignificant
associationbetween45TT
carriersandCA
D(P
=0033)
(ii)P
ositive
significant
associationbetween276G
GcarriersandCA
D(P
=0023)
Rahimietal2012
[83]
eNOSG8
94T
CETP
B1
102CA
DD
M105
CADN
D101
DMand
92ND45ndash66
yrM
FKe
rmanshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
concom
itant
presence
ofNOS3
TalleleandCE
PTB1
allelewith
T2DM
(P=000
4)andCA
D(119875=0002)
Assalietal2011[84]
AT1RA116
6C145CA
DD
Mand164CA
D
lt50
andge50
yrM
FMashh
adCa
secontrol
PCR-RF
LPPo
sitives
ignificantassociatio
nof
ACandCC
carrierswith
DM
(119875=001)
Emam
gholipou
retal2009
[85]
Resistin
minus420C
G113CA
Dwith
andwith
outD
M
58plusmn9yrM
FTehran
Crosssectio
nal
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDM
(119875=0009)
10 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Fallahetal2010
[86]
MMP-3minus1612
5A6A
305CA
DD
Mand313DM
61plusmn9yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetween6A
6AcarriersandCA
S(P
=0008)
Vaisi-Raygani
etal2010
[87]
BChE
KG1
615A
APO
EE2
E3E4
118DM162
CADN
D172
DMCADand
179healthy
42ndash6
8yrMF
Kerm
anshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GAA
Aand
E4carrierswith
CADandDM
(Plt005)
Positives
ignificantassociatio
nof
BChE
KAp
oE4carrierswith
CADand
DM
(Plt005)
Sign
ificant
associationof
BChE
KAp
oE4with
lipid
profi
le(119875lt005)
Rahimietal2009
[88]
Factor
VLeidenG
1691A
Prothrom
binG2
0210A
MTH
FRC677T
65CA
DD
M52CA
DN
Dand
59healthy46
064y
rMF
Kerm
anshah
Case
control
PCR-RF
LPNon
significance
Nakhjavanietal2007
[89]
ACEID
82DM
with
hypertensio
nand87
DM
with
outh
ypertension
49ndash6
3yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
hypertensio
n(P
=0026)
Vaisi-Raygani
etal2007
[90]
Apolipop
roteinE2E3
E4
152CA
DD
M262
CADN
D
and300healthy35ndash73y
rMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nof
E2andE4
allelec
arrie
rswith
CAD(Plt0001)
T2DM
patie
ntsa
ndneph
ropathy
Rahimietal2013
[91]
eNOS4abG
894T
63T2
DMm
icroalbu
minuria
57T2
DMm
acroalbu
minuria
52T2
DMnormoalbum
inuria
121D
Nand
101h
ealth
y45ndash6
6yrMF
Kerm
anshah
Case
control
PCR
PCR-RF
LP
Positives
ignificantassociatio
nof
4aor
894T
allelecarriersand
macro-(P=001)o
rmicroalbu
minuria(P
=002)
Rahimietal2013
[92]
AT2R
minus1332GA
28T2
DMm
icroalbu
minuria
22T2
DMm
acroalbu
minuria
20T2
DMnormoalbum
inuria
and112healthy43ndash6
3yrMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(P
=0016)
Shahsavare
tal2013
[93]
SUMO4163A
G(M
55V)
50T2
DD
Nand50
T2DM
non-DN25ndash45
yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(Plt005)
Arababadi
etal2012
[94]
IL-10minus592C
A100T2
DMnon
-DN100
T2DMD
Nand100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDN
(119875=0001)
Journal of Diabetes Research 11
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2012
[95]
VEG
F+4
05G
C255T2
DMm
icroalbu
minuria
and235T2
DMnon
albu
minuric
50ndash6
7yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersand
albu
minuria(P
=0002)
Rahimietal2012
[96]
MTH
FRA1298C
C677T
ACEID
72T2
DMM
icAlb
68T2
DMM
acAlband72
T2DMnon
-DN46ndash
65yrM
FKe
rmanshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nof
ACED677T(P
=0035)
and
ACED12
98C(P
=0012)
carrierswith
macroalbu
minuria
Rahimietal2012
[97]
eNOSG8
94T
ACEID
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nbetweenAC
EDcarriersand
macroalbu
minuria(P
=0035)
Feleh
garietal2011[98]
ACEID
68T2
DMm
acroalbu
minuria
and72
T2Dmnormoalbum
inuria
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR
Non
significance
Jafarietal2011[99]
eNOSG8
94T
MTH
FRC677TA
1298C
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
eNOST1298
CandeN
OS
T677Tcarrierswith
macroalbu
minuria(Plt005)
(ii)S
ignificantassociatio
nof
eNOSGT+
TTcarrierswith
lipid
profi
le(Plt005)
Rahimietal2011[100]
ACEID
Factor
VLeidenG
1691A
217mean55both
Kerm
anshah
Case
control
PCR
PCR-RF
LPNon
significance
Arababadi2010[101]
IL-4minus590C
T100T2
DMD
Nand150healthy
33ndash4
7yrMF
Rafsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenCT
carriersandDN
(119875lt0001)
Nosratabadi
etal2010
[102]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DMnon
-DN100
T2DMD
Nand
100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandDN
(119875=0012)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandDN
Rahimietal2010
[103]
MTH
FRC677TA
1298C
72T2
DMm
icrolbum
iunira
68T2
DMm
acroalbu
minuria
and72
T2DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
677T1298C
and677T
1298C
carrierswith
macroalbu
minoria
(Plt0001)
(ii)P
ositive
significant
associationof
CT+T
Tand
677T
1298Ccarrierswith
microalbu
minuria(Plt0001)
12 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2009
[104]
ACEID
129T
2DMm
icrolbum
iunira
48T2
DMm
acroalbu
minuria
and145T
2DMnormoalbum
inuria
594plusmn85y
rMF
Tehran
Crosssectio
nal
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
progressionof
albu
minuria
(119875lt001)b
utno
tits
developm
ent
Nikzamiretal2006
[105]
ACEID
85T2
DMD
N85T2
DMnon
-DN
and91
healthy37ndash6
7yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(119875=0006)b
utno
tDN
T2DM
patie
ntsa
ndretin
opathy
Abbasietal2013
[106]
GST
M1n
ullp
ositive
80DRand80
healthy
30ndash70y
rMF
Rasht
Case
control
ARM
S-PC
RNullgenotypes
ignificant
association
Plt005
Dadbinp
oure
tal2013
[107]
(i)GST
M1n
ullp
ositive
(ii)G
STT1nullp
ositive
57DRand58
non-DR
35ndash6
5yrMF
Yazd
Case
control
Multip
lexPC
R
(i)Nullgenotypeo
fGST
M1o
rGST
T1sig
nificantassociatio
n(119875=004)
(ii)N
onsig
nificantassociatio
nof
GST
T1nu
llcarrierswith
DR
Fegh
hietal2011[108]
VEG
F+4
05G
C119
diabeticsw
ithPD
Rand279
diabeticsw
ithNPD
R47ndash6
6yrMF
Ahvaz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersanddiabetic
retin
opathy
(P=0005)
T2DM
patie
ntsa
ndfoot
ulcer
Amolietal2011[109]
(i)VEG
Fminus7C
T(ii)V
EGFminus2578CA
247T2
DM
with
DFU
241
T2DM
with
outD
FUand
98healthy
43ndash6
4MF
Tehran
Case
control
ARM
S-PC
R
(i)Non
significantassociatio
nof
minus7C
Tcarrierswith
DFU
(ii)P
ositive
significant
associationbetweenAAcarriers
andDFU
(P=003)
SNPsin
glenu
cleotid
epo
lymorph
ismT
1DMtype1d
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4T2
DMtype2diabetes
mellitusP
CRp
olym
erasechainreactio
nRF
LPrestrictio
nfragmentlengthpo
lymorph
ismILinterle
ukinSS-PC
Rsequ
ence
specificP
CRV
DR
vitamin
DreceptorT
AP2
transpo
rter
2AT
P-bind
ingcassetteA
RMS-PC
Ram
plificatio
nrefractory
mutationsyste
mPC
RPC
R-SSPPC
Rsin
glespecificprim
erT
GF120573
transform
inggrow
thfactor120573D
Md
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4
MODY
maturity
onsetd
iabeteso
fthe
youn
gHNF-
1120572h
epatocytenu
clear
factor
1120572M
VCm
icrovascular
complicationsT
CF7L
2transcrip
tionfactor
7-lik
e2PC
R-SSCA
PCR
singlestr
andconformationpo
lymorph
ismanalysis
ER120572estr
ogen
receptor120572N
D
nond
iabeticsTC
totalcholesterolTG
trig
lycerid
esP
PAR-1205742peroxisomep
roliferator-activates
receptor120574G
LP-1R
glucagon
-like
peptid
1receptorAPO
apo
lipop
roteinC
XCL5chemokineC
-X-C
motifligand
5SD
F-1120573stro
malderiv
edfactor-1120573IRS
1amp2insulin
receptor
substrate1amp
2GSTglutathione-S-tr
ansfe
raseSLC
30A8solublecarrier3
0A8KC
NJPo
tassium
inwardly-rectify
ingchanneleN
OSendo
thelial
nitricoxidesynthaseVNTR
variablen
umbero
ftandem
repeatsEN
PP1ectoenzymen
ucleotidep
yrop
hosphateph
osph
odieste
rase1SU
MOsmallubiqu
itin-lik
emod
ifier4UCP
2un
coup
lingp
rotein
2MTH
FR
methylenetetrahydrofolateredu
ctaseIFN120574interferon120574C
CR5C-
Cchem
okiner
eceptortype5
INSR
insulin
receptorC
SGE
conformation-sensitive
gelelectroph
oresis
ACE
angiotensin
Icon
vertingenzyme
HFE
hem
ochrom
atosisgenePTP
N1proteintyrosin
Phosph
atase1B
CADcoron
arya
rteryd
iseaseCE
TPcho
leste
ryleste
rtransferp
roteinA
T1R
angiotensin
IreceptorMMP3
matrix
metalloproteinase
3CA
Scoronary
artery
steno
sisB
ChEK
Butyrylcho
linesteraseK
DNdiabetic
neph
ropathyAT
2Rang
iotensin
IIreceptorV
EGFvascularepith
elium
grow
thfactorD
Rdiabeticretin
opathy
PDR
proliferativ
ediabetic
retin
opathy
NPD
Rno
n-PD
RDFU
diabetic
foot
ulcer
Journal of Diabetes Research 13
321 T1DM Related Genes All the studies in this subgroupincluding 12 studies [22ndash33] were in a case control studydesign using PCR (polymerase chain reaction) [33] PCR-RFLP (restriction fragment length polymorphism) [22 2325 26 32] PCR-SSP (single specific primer) [24 28ndash32]and ARMS-PCR (amplification refractory mutation systemPCR) [27] method In all studies both men and women wereincluded and the overall 2519 subjects were under 40 yearsold
Association of interleukins including IL-18 (interleukin)and IL-12 with T1DM revealed that the minus137CG polymor-phism of IL-18 had significant association with T1DM (119875 =0037 119875 = 00001) while no significant relation was observedbetween minus607AC variant of this gene and T1DM [24 28]Investigating IL-12 also showed that there was a significantassociation between +1188AC polymorphism of this geneand T1DM (119875 = 0035) [30]
In 2 studies the association of +49AG variant of CTLA-4 (cytotoxic T lymphocyte associated antigen 4) was investi-gated and it was revealed that there was a positive significantassociation between AG genotype and T1DM (119875 = 001 119875 lt0001) [22 32] One of these studies also revealed that therewas a negative relation betweenAA genotype and T1DM [32]
Vitamin D receptor (VDR) was investigated in 2 studies[25 26] Both of them assessed the association of FokI BsmIApaI and TaqI variants of VDR with T1DM In one studywhichwas performed on 114 subjects Aa (119875 = 0003) FF (119875 =0008) and Bb (119875 = 0014) genotypes were shown to be pos-itively associated with T1DM but no significant associationwas observed between TaqI polymorphism and T1DM [25]Another study which was performed on 187 subjects showedno significant association between T1DM and FokI BsmIand ApaI However TT genotype was observed to be morefrequent in controls (119875 = 0007) and negatively associatedwith T1DM [26]
Different polymorphisms of TAP2 and their associationwith T1DM were investigated in 191 subjects It was shownthat Ile379Val and Stop687Gln had significant associationwith T1DM (119875 = 0001 and 119875 = 0013 resp) Other variantsof TAP2 (transporter 2 ATP-binding cassette) includingAla565Thr Arg651Cys and Ala665Thr were not associatedwith T1DM significantly [27]
Association of alleles A2ndashA9 of CD4 with T1DM wasassessed in 200 subjects It was revealed that A3 allele hadnegative (119875 = 0025) and A5 had positive (119875 = 0001)significant association with T1DM [33]
Association of some other genes including osteopontin(rs1126772 polymorphism) integrin 1205724 (rs1449263 polymor-phism) CD44 (rs8193 polymorphism) and TGF120573 (trans-forming growth factor) (+915CG polymorphism) was alsoinvestigated in 2 studies and no significant relation wasobserved between these variants and T1DM [23 29]
322 MODY In this category only one study was found [34]and the association of Val255Met polymorphism of HNF120572and diabetes was investigated in 101 subjects includingMODY subjects their relatives and healthy controls [34]Thestudy was designed as a case control association study andPCR-RFLP and direct sequencing was used for genotyping
of variants Val255Met mutation in this investigation wasobserved in MODY subjects and their relatives but not incontrol group
323 T2DM Related Genes In this subgroup 42 studieswere assessed and all of them were designed as case controlassociation studies [22 35ndash68 70ndash75] except for one whichwas cross sectionally designed [69] In 33 studies PCR- RFLPwas used for genotyping [22 36ndash38 40ndash54 56 58ndash61 63ndash66 69 72ndash75] In 5 of them PCR was used [35 57 62 70 71]and the remaining studies PCR-SCA [39] real-timePCR [55]ARMS-PCR [66] Gap PCR [67] and CSGE (conformation-sensitive gel electrophoresis) sequencing [68] as the genotyp-ing method were applied
Association between two polymorphisms of TCF7L2including rs7903146 (CT) and rs12255372 (GT)was assessedin three studies [38 48 53] In one study investigatingrs7903146 (CT) in 466 subjects significant difference in thefrequency of CC and CT genotypes was observed betweenT2DM and control group (119875 = 0045) [38] However inanother study this polymorphism showed a positive signifi-cant associationwith TT genotype in T2DM (119875 = 0008) [53]Investigation of rs12255372 (GT) polymorphism of TCF7L2in another study showed that among 491 subjects there wasa positive significant association between TT carriers andT2DM (119875 = 0014) [48]
Investigating the association of calreticulinwith T2DM in650 subjects showed two mutations only in case group 9 bpdeletion of 397ndash399 codons and GgtT mutation at IVSII-142[39]
Association of estrogen receptor 120572 and its PvuII(PPPppp) and XbaI(XXXxxx) polymorphism with T2DM intwo studies was assessed [40 49] In one study the significantassociation of PvuII and XbaI polymorphisms with T2DMwas observed (119875 = 0014 and 119875 = 0002 resp) [40] Inanother study it was revealed that pooled Pp+pp and XX+xxmale carriers have positive significant associationwithT2DM(119875 = 0001 and 119875 = 0026 resp) [49]
Association of Pro12Ala polymorphism of PPAR120574 withT2DMwas investigated in three studies [41 69 75] Negativesignificant association of AlaAla genotype with T2DM wasobserved in two studies (119875 = 0003) [41 75] AlaPro carrierswere shown to be positively associated in one study [41] andnegatively associated in another study [75] with T2DM (119875 lt0001 and 119875 = 0003 resp) However in the third studyno significant association was observed between Pro12Alapolymorphism of PPAR120574 and T2DM [69]
Association of different polymorphisms of ApoAI withT2DM was investigated in two studies [43 72] In one studyinvestigation of MSPI polymorphism showed no significantassociation with T2DM [43] In another study it was shownthat G-75A polymorphism of ApoAI was not associated withT2DM while a significant association was found betweenC+83T polymorphism and T2DM (119875 = 0028) [72]
Two studies assessed the association of minus156GgtC poly-morphism of CXCL5 with T2DM [44 65] In one studypositive significant association of GC carriers (119875 = 0006)and negative association of GG carriers (119875 = 001) was foundbetween diabetic patients and healthy controls [44] and
14 Journal of Diabetes Research
in another study positive significant association was foundbetween GC or CC carriers and T2DM (119875 = 0009) [64]
Adiponectin and its association with T2DM were inves-tigated in two studies [56 73] In one study two variantsincluding +45TG and minus11391GA were investigated but nosignificant relation was found between these two polymor-phisms and T2DM [56] However in another study investi-gating +45TG polymorphism of adiponectin it was revealedthat nonobese T2DM subjects had significantly higher TTgenotype (119875 = 004) [73]
In one study that investigated insulin receptor gene thefollowing mutations were found only in T2DM 511CgtA514TgtG 586 and 628TgtA on exon 2 694GgtC 680GgtA onexon 3 1627AgtT on exon 8 ATgtTG on intron 9 2007CgtCTon exon 9 2595CgtCT and 2669GgtCG on exon 13 2706 and2717CgtG 2752CgtT and 2753CgtG on exon 14 and 3471TgtAand 3516TgtG on exon 19 These mutations were not seen incontrol subjects [68]
Other variants which had significant association withT2DM included haptoglobin (allele 2-2) leptin (G-2548Apolymorphism) paraoxonase 2 (Ser311Cys polymorphism)GST (glutathione-S-transferase) M1 and GSTM1GSTT1interaction calpain-10 (SNP (single nucleotide polymor-phism) 43) IRS-1 (G972R polymorphism) and IRS-2(G1057D polymorphism) VDR (vitamin D receptor) (TaqIpolymorphism) KCNJ11 (E23K polymorphism) eNOS(endothelial nitric oxide synthase) VNTR (intron 4 ab pol-ymorphism) resistin (minus420CG polymorphism) and ACE(InsertionDeletion) [35ndash37 45 47 50 55 57 58 64 70]
In contrast to above variants CTLA4 (+49AG poly-morphism) HNF-1120572 (Ala98Val polymorphism) GLP-1R(glucagon-like peptid 1 receptor) (Thr149Met polymor-ohism) SLC30A8 (Arg325Trp polymorphism) GSTP1(Ile105Val polymorphism) glucokinase (minus30GA polymor-phism) SDF-1120573 (stromal derived factor -1 120573) (G801A poly-morphism) ApoE (apolipoprotein E) ENPP1 (ectoenzymenucleotide pyrophosphate phosphodiesterase 1) (K121Q poly-morphism) SUMO4 (small ubiquitin-like modifier 4)Met55Val polymorphism) MTHFR (C677T polymorphism)UCP2 (uncoupling protein 2) (minus866GA polymorphism)5HTTLPR IL-4 (minus590CT polymorphism) IFN-120574 (inter-feron 120574) (+874TA polymorphism) CCR5 (C-C chemokinereceptor type 5) (12057532mutation) HFE (hemochromatosisgene) (H63D C282Y PTPN1 (protein tyrosin Phosphatase1B)minus51delA minus451AgtG minus467TgtC minus1023CgtA minus1045GgtAminus1286 3 bp del ACA minus1291 9 bp del CTAGACTAA poly-morphisms) were not significantly associated with T2DM[22 42 46 50ndash52 54 59ndash63 66 67 71 74]
324 Genes Related to Insulin Resistance In this subgroupfour studies were assessed and all were designed as case-control association studies Three studies used PCR-RFL [7678 79] and one study used real-time PCR [77] for genotyping
The studies assessed in this subgroup showed a positiveassociation of TG carriers of +45TG polymorphism ofadiponectin (119875 = 0032) and Ala allele carriers of Pro12Alapolymorphism of PPAR120574 (119875 = 0036) with T2DM [76 77]A positive significant association of ff carriers of VDR wasalso shown (FokI polymorphism) (119875 = 002) and negative
association of 148insG carriers of PTPN1 (148insG polymor-phism) (119875 = 0041) with insulin resistance index [7879] However no significant association was shown betweenadiponectin receptor-2+795GA and T2DM [76]
325 Genes Related to Cardiovascular Disease in DiabetesDesign of all 11 studies in this subgroup was case-controlassociation study [80ndash84 86ndash90] except one study which wasdesigned as cross sectional [85] PCR-RFLP was used in all ofthem for genotyping [80ndash88 90] except in one study whichused ARMS-PCR method [89]
Paraoxonase 1 (163TA polymorphism) was the only vari-ant in this subgroup which was not significantly associatedwith atherosclerosis risk in T2DM [80] Investigation ofanother polymorphism of Paraoxonase 1 (Q192R) revealedthat diabetics with CAD had significant increase in RRgenotype (119875 lt 005) [81]
Investigating B1 and B2 alleles of CETP TaqI B allele in400 subjects showed that pooling of B1B1+B1B2 and B1B1genotypes had significant association with T2DM and CAD(119875 lt 001) On the other hand assessing the G894T poly-morphism of eNOS showed positive significant associationbetween TG and TT carriers and CAD (119875 lt 005) It was alsoshown that concomitant presence of NOS3 T allele and CEPTB1 allele was significantly associated with T2DM (119875 = 0004)and CAD (119875 = 0002) [83]
Investigation of apolipoprotein E (E2 E3 and E4) allelesshowed the association of E2 and E4 alleles with CAD(119875 lt 0001) [84 87] Also it was shown that interactionof butyrylcholinesterase (BChE K) and apolipoprotein E(ApoE) was associated significantly with CAD and diabetesApoE4BChE K had significant association with lipid profilesas well (119875 lt 005) [87]
Adiponectin +276GT and +45TG were significantlyassociated with CAD (119875 = 0023 and 0033 resp) [82] whileinvestigating minus1612 5A6A polymorphism of MMP-3 (matrixmetalloproteinase 3) showed a significant association withCAS (coronary artery stenosis) (119875 = 0008) [86]
In addition A1166C polymorphism of AT1R (angiotensinI receptor) and minus420CG polymorphism of resistin in dia-betic patients with CAD revealed significant association withdiabetes 119875 = 001 and 119875 = 0009 respectively [84 85]
Another study showed insertion(I)deletion(D) polymor-phismof angiotensin converting enzyme (ACE)DDgenotypewas significantly associated with higher blood pressure (119875 =0026) [89]
Factor V Leiden (G1691A polymorphism) prothrombin(G20210A polymorphism) and MTHFR (methylenetetrahy-drofolate reductase) (C677T polymorphism) were the vari-ants which were not significantly associated with CAD andT2DM in this subgroup [88]
326 Genes Related to Diabetic Nephropathy All of 15 studiesin this subgroup were designed as case-control associationstudies [91ndash106] In 7 studies PCR-RFLP was used forgenotyping [92ndash95 99 102 103] in four studies PCRwas used[98 101 104 105] and in 4 of them both PCR and PCR-RFLPwere used [91 96 97 100]
Journal of Diabetes Research 15
Studying the association of 163AG polymorphism ofSUMO4 showed a positive significant association betweenAA carriers and diabetic nephropathy (119875 lt 005) [93]
Studying the interaction of eNOS4ab and G894Trevealed positive significant association between 4a or 894Tallele carriers and macro- and microalbuminuria (119875 = 001119875 = 002 resp) [91] It was observed that the interaction ofeNOS (G894T polymorphism) andACE (ID alleles) was sig-nificantly associated with more frequent macroalbuminuria(119875 = 0035) [97]
It has also been shown that interaction of eNOS (G894Tpolymorphisms) and MTHFR (C677T and A1298C poly-morphisms) eNOS T1298 C and eNOS T677 T carriershad positive significant association with macroalbuminuriaIn addition significant association of eNOS GT+TT carrierswith lipid profile (119875 lt 005) was shown in this study [99]
C677T andA1298C polymorphisms ofMTHFRwere alsoinvestigated in another study revealing that 677T 1298Cand 677T1298C carriers were significantly associated withmacroalbuminuria (119875 lt 0001) Positive significant asso-ciation when pooling CT+TT genotypes and 677T1298Cwas also found with microalbuminuria (119875 lt 0001) [103]Investigating the interaction of MTHFR (A1298C C677Tpolymorphisms) and ACE (ID alleles) showed a positivesignificant association of ACE D677T (119875 = 0035) and ACED1298C (119875 = 0012) genotypeswithmacroalbuminuria [96]
ACE (ID alleles) polymorphisms were investigated inthree studies In one study positive significant association(119875 lt 001) between DD carriers and progression but notdevelopment of albuminuria was observed [104] In anotherstudy in nephropathic subjects association of DD carriersand T2DM (119875 = 0006) but not nephropathy was revealed[105] However another study did not show significant asso-ciation of ACE with macroalbuminuria [98] Interaction ofACE (ID alleles) with Factor V Leiden (G1691A polymor-phism) was not significant [100]
Association of interleukins including IL-4 and IL-10 withdiabetic nephropathy was also investigated in two studiesStudy of minus592CA polymorphism of IL-10 revealed positivesignificant association between CC carriers and nephropathy(119875 = 0001) [94] and study ofminus590CTpolymorphismof IL-4revealed positive significant association between CT carriersand nephropathy (119875 lt 0001) [101]
Other significant associations between variants and dia-betic nephropathy included AT2R (angiotensin II recep-tor) (minus1332GA polymorphism) VEGF (vascular epitheliumgrowth factor) (+405GC polymorphism) and VDR (TaqIpolymorphism) [92 95 102] ApaI polymorphism of VDRwas not significantly associated with diabetic nephropathy[102]
327 Genes Related to Diabetic Retinopathy All of the 3studies in this subgroup were conducted as case-controlassociation studies [106ndash108]
Investigating nullpositive genotype of GSTM1 in a studywhich used ARMS-PCR for genotyping revealed that nullgenotype is significantly associated with diabetic retinopathy(119875 lt 005) [106] This result was confirmed in another study
by using multiplex PCR as genotyping [107] although nosignificant association between GSTT1 and retinopathy wasfound in this study [107]
Investigating +405GC polymorphism of VEGF alsorevealed positive significant association between GG carriersand diabetic retinopathy (119875 = 0005) [108]
328 Genes Related to Diabetic Foot Ulcer In this subgrouponly one study was found [109] which was case-controldesigned and used ARMS-PCR for genotyping In this studyassociation of minus7CT and minus2578CA polymorphisms ofVEGF with diabetic foot ulcer (DFU) was investigated and apositive significant association betweenAA carriers andDFU(119875 = 003) was observed But no significant association wasfound between minus7CT of VEGF and DFU [109]
4 Discussion
Diabetes mellitus is the eighth most frequent disease leadingcause of death throughout the world and now ranks the fifthfollowing communicable diseases cardiovascular diseasecancer and injuries [110] Prevalence of diabetes mellitus isincreasing worldwide [6]
Type 2 diabetes is the most frequent type of diabetesmellitus [110 111] Multiple genes and environmental factorsaffect the prevalence of T2DM Systematic review and meta-analysis studies have assessed the association between dif-ferent genes and T2DM Glutathione-S-transferase includingGSTMI GSTM1 and GSTP1 are important genes and theirassociation with diabetes has been investigated in two meta-analysis studies [112 113] It was revealed that null genotypeof both GSTM1 and GSTT1 could be as a risk factor fordiabetes while no significant association was found betweenGSTP1 and diabetes [112 113] These results are in linewith our finding and confirming the association of the nullgenotype of GSTT1 and GSTM1 with T2DM in Iranianpopulation [50] The relation between GSTT1 and GSTM1and diabetic retinopathy has also been shown in Iranianpopulation [106 107]
MTHFR is another important gene in association withT2DM and other related complications No associationof C677T polymorphism of MTHFR gene was found inAfricans Asians and Caucasians [114] MTHFR is a genewhich is involved in DNA methylation and synthesis andregulated folate activity It has been reported that mutanthomozygote and heterozygote of C677T polymorphism ofMTHFR increase plasma homocysteine which is an impor-tant factor leading to diabetic nephropathy (DN) and as aresult C677T polymorphism of MTHFR can be associatedwith the development of DN In Caucasians this associationhas also been observed [115] In Iranian population in linewith other populations no significant association was foundbetween MTHFR polymorphisms and T2DM [63] althoughsignificant association of 677T and 1298C alleles with diabeticnephropathy was observed [87] Interaction of two polymor-phisms and also interaction of MTHFR polymorphisms withother genes such as ACE and eNOS showed an associationwith development of DN [96 99]
16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
8 Journal of Diabetes ResearchTa
ble1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
KazemiA
rababadi
etal2009
[66]
IL-4minus590C
TIFN-120574+874T
A160T2
DM
and160healthy
38plusmn9y
rMF
Rafsanjan
Case
control
PCR-RF
LPARM
S-PC
RNon
significance
Arababadi
etal2009
[67]
CCR5
12057532mutation
200T2
DM
and300healthy
40plusmn9y
rMF
Rafsanjan
Case
control
Gap-PCR
Non
significance
Kazemietal2009
[68]
INSR
128T2
DMgt
40yrM
FTehran
Case
control
PCR
CSGE
sequ
encing
Follo
wingmutations
werefou
ndon
lyin
T2DM
511CgtA514Tgt
G586and
628TgtAon
exon
2694GgtCand680GgtAon
exon
31627AgtTon
exon
8ATgtTG
onintro
n9
2007Cgt
CTon
exon
92595Cgt
CTand2669GgtCGon
exon
132706
and2717Cgt
G2752CgtT
2753Cgt
Gonexon
143471Tgt
Aand3516Tgt
Gon
exon
19
Mirz
aeietal2009
[69]
PPAR120574
2Pro12A
la78
norm
al78ob
ese78
T2DM
and78
obeseT
2DM25ndash64
yr
MF
Tehran
Crosssectio
nal
PCR-RF
LPNon
significance
Nikzamiretal2008
[70]
ACEinsertion(I)
deletion(D
)170T2
DM
and144healthyMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(P=002)
Sharifi
etal2008
[71]
HFE
H63D
C282Y
101T
2DM
and101h
ealth
y55plusmn11yrM
FZa
njan
Case
control
PCR
Non
significance
Besharatietal2007
[72]
(i)Ap
oA-IG
-75A
(ii)A
poA-
IC+8
3T215subjects26ndash
64yrM
FTehran
Crosssectio
nal
PCR-RF
LP
(i)Non
significantassociatio
nbetweenG-75A
carriersand
T2DM
(ii)P
ositive
significant
associationbetweenCT
carriers
andT2
DM
(P=0028)
Hasani-R
anjbar
etal2007
[73]
Adipon
ectin
+45TG
80T2
DM
obese72
T2DM
nono
beseand
70healthy
25ndash6
4yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenTT
carriersand
nono
bese
T2DM
(P=004)
Meshk
anietal2007
[74]
PTPN
1minus51delA
minus451AgtGminus467TgtC
minus1023Cgt
Aminus1045GgtAminus1286
3bpdel
ACAminus1291
9bpdel
CTAG
ACTA
A
174T2
DM
and412healthy
23ndash79MF
Tehran
Case
control
PCR
sequ
encing
PCR-RF
LPNon
significance
Meshk
anietal2007
[75]
PPAR120574
Pro12Ala
412T2
DM
and284healthy
23ndash79y
rMF
Tehran
Case
control
PCR-RF
LPNegatives
ignificantassociatio
nbetweenProAlaor
AlaA
lacarriersandT2
DM
(P=0003)
Journal of Diabetes Research 9
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
T2DM
patie
ntsa
ndinsulin
resistance
Nam
varanetal2012
[76]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin
receptor-2+795G
A
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTG
carriersandT2
DM
(P=0032)
(ii)N
onsig
nificantassociatio
nbetween+7
94GA
carriersand
insulin
resistance
Nam
varanetal2011[77]
PPAR120574
Pro12Ala
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
Realtim
ePCR
Positives
ignificantassociatio
nbetweenAlaallelecarriersand
T2DM
(P=0036)
Hossein-nezhadetal2009
[78]
VDRFokI
(FFFfff
)105T2
DM55plusmn10yrM
FTehran
Case
serie
sPC
R-RF
LPPo
sitives
ignificantassociatio
nbetweenffcarriersandinsulin
resistanceind
ex(P
=002)
Moo
sapo
oretal2007
[79]
PTPN
1148insG
71T2
DM
and264ND
20ndash80y
rMF
Tehran
Case
control
PCR-RF
LP
Negatives
ignificantassociatio
nbetween148insGcarriersand
insulin
resistanceind
ex(119875=0041)
T2DM
patie
ntsa
ndheartd
iseases
Bayatm
akoo
etal2013
[80]
Paraoxon
ase116
3TA
(L55M)
105CA
DD
Mand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPNon
significance
Bayatm
akoo
etal2012
[81]
Paraoxon
ase1575Ggt
A(Q
192R
)105DMCADand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenRR
carriersand
CADD
M(Plt005)
Estegh
amatietal2012
[82]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin+276G
T114
CADD
Mand127DM
42ndash71yrMF
Tehran
Case
control
PCR-RF
LP
(i)Negatives
ignificant
associationbetween45TT
carriersandCA
D(P
=0033)
(ii)P
ositive
significant
associationbetween276G
GcarriersandCA
D(P
=0023)
Rahimietal2012
[83]
eNOSG8
94T
CETP
B1
102CA
DD
M105
CADN
D101
DMand
92ND45ndash66
yrM
FKe
rmanshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
concom
itant
presence
ofNOS3
TalleleandCE
PTB1
allelewith
T2DM
(P=000
4)andCA
D(119875=0002)
Assalietal2011[84]
AT1RA116
6C145CA
DD
Mand164CA
D
lt50
andge50
yrM
FMashh
adCa
secontrol
PCR-RF
LPPo
sitives
ignificantassociatio
nof
ACandCC
carrierswith
DM
(119875=001)
Emam
gholipou
retal2009
[85]
Resistin
minus420C
G113CA
Dwith
andwith
outD
M
58plusmn9yrM
FTehran
Crosssectio
nal
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDM
(119875=0009)
10 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Fallahetal2010
[86]
MMP-3minus1612
5A6A
305CA
DD
Mand313DM
61plusmn9yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetween6A
6AcarriersandCA
S(P
=0008)
Vaisi-Raygani
etal2010
[87]
BChE
KG1
615A
APO
EE2
E3E4
118DM162
CADN
D172
DMCADand
179healthy
42ndash6
8yrMF
Kerm
anshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GAA
Aand
E4carrierswith
CADandDM
(Plt005)
Positives
ignificantassociatio
nof
BChE
KAp
oE4carrierswith
CADand
DM
(Plt005)
Sign
ificant
associationof
BChE
KAp
oE4with
lipid
profi
le(119875lt005)
Rahimietal2009
[88]
Factor
VLeidenG
1691A
Prothrom
binG2
0210A
MTH
FRC677T
65CA
DD
M52CA
DN
Dand
59healthy46
064y
rMF
Kerm
anshah
Case
control
PCR-RF
LPNon
significance
Nakhjavanietal2007
[89]
ACEID
82DM
with
hypertensio
nand87
DM
with
outh
ypertension
49ndash6
3yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
hypertensio
n(P
=0026)
Vaisi-Raygani
etal2007
[90]
Apolipop
roteinE2E3
E4
152CA
DD
M262
CADN
D
and300healthy35ndash73y
rMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nof
E2andE4
allelec
arrie
rswith
CAD(Plt0001)
T2DM
patie
ntsa
ndneph
ropathy
Rahimietal2013
[91]
eNOS4abG
894T
63T2
DMm
icroalbu
minuria
57T2
DMm
acroalbu
minuria
52T2
DMnormoalbum
inuria
121D
Nand
101h
ealth
y45ndash6
6yrMF
Kerm
anshah
Case
control
PCR
PCR-RF
LP
Positives
ignificantassociatio
nof
4aor
894T
allelecarriersand
macro-(P=001)o
rmicroalbu
minuria(P
=002)
Rahimietal2013
[92]
AT2R
minus1332GA
28T2
DMm
icroalbu
minuria
22T2
DMm
acroalbu
minuria
20T2
DMnormoalbum
inuria
and112healthy43ndash6
3yrMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(P
=0016)
Shahsavare
tal2013
[93]
SUMO4163A
G(M
55V)
50T2
DD
Nand50
T2DM
non-DN25ndash45
yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(Plt005)
Arababadi
etal2012
[94]
IL-10minus592C
A100T2
DMnon
-DN100
T2DMD
Nand100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDN
(119875=0001)
Journal of Diabetes Research 11
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2012
[95]
VEG
F+4
05G
C255T2
DMm
icroalbu
minuria
and235T2
DMnon
albu
minuric
50ndash6
7yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersand
albu
minuria(P
=0002)
Rahimietal2012
[96]
MTH
FRA1298C
C677T
ACEID
72T2
DMM
icAlb
68T2
DMM
acAlband72
T2DMnon
-DN46ndash
65yrM
FKe
rmanshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nof
ACED677T(P
=0035)
and
ACED12
98C(P
=0012)
carrierswith
macroalbu
minuria
Rahimietal2012
[97]
eNOSG8
94T
ACEID
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nbetweenAC
EDcarriersand
macroalbu
minuria(P
=0035)
Feleh
garietal2011[98]
ACEID
68T2
DMm
acroalbu
minuria
and72
T2Dmnormoalbum
inuria
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR
Non
significance
Jafarietal2011[99]
eNOSG8
94T
MTH
FRC677TA
1298C
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
eNOST1298
CandeN
OS
T677Tcarrierswith
macroalbu
minuria(Plt005)
(ii)S
ignificantassociatio
nof
eNOSGT+
TTcarrierswith
lipid
profi
le(Plt005)
Rahimietal2011[100]
ACEID
Factor
VLeidenG
1691A
217mean55both
Kerm
anshah
Case
control
PCR
PCR-RF
LPNon
significance
Arababadi2010[101]
IL-4minus590C
T100T2
DMD
Nand150healthy
33ndash4
7yrMF
Rafsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenCT
carriersandDN
(119875lt0001)
Nosratabadi
etal2010
[102]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DMnon
-DN100
T2DMD
Nand
100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandDN
(119875=0012)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandDN
Rahimietal2010
[103]
MTH
FRC677TA
1298C
72T2
DMm
icrolbum
iunira
68T2
DMm
acroalbu
minuria
and72
T2DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
677T1298C
and677T
1298C
carrierswith
macroalbu
minoria
(Plt0001)
(ii)P
ositive
significant
associationof
CT+T
Tand
677T
1298Ccarrierswith
microalbu
minuria(Plt0001)
12 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2009
[104]
ACEID
129T
2DMm
icrolbum
iunira
48T2
DMm
acroalbu
minuria
and145T
2DMnormoalbum
inuria
594plusmn85y
rMF
Tehran
Crosssectio
nal
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
progressionof
albu
minuria
(119875lt001)b
utno
tits
developm
ent
Nikzamiretal2006
[105]
ACEID
85T2
DMD
N85T2
DMnon
-DN
and91
healthy37ndash6
7yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(119875=0006)b
utno
tDN
T2DM
patie
ntsa
ndretin
opathy
Abbasietal2013
[106]
GST
M1n
ullp
ositive
80DRand80
healthy
30ndash70y
rMF
Rasht
Case
control
ARM
S-PC
RNullgenotypes
ignificant
association
Plt005
Dadbinp
oure
tal2013
[107]
(i)GST
M1n
ullp
ositive
(ii)G
STT1nullp
ositive
57DRand58
non-DR
35ndash6
5yrMF
Yazd
Case
control
Multip
lexPC
R
(i)Nullgenotypeo
fGST
M1o
rGST
T1sig
nificantassociatio
n(119875=004)
(ii)N
onsig
nificantassociatio
nof
GST
T1nu
llcarrierswith
DR
Fegh
hietal2011[108]
VEG
F+4
05G
C119
diabeticsw
ithPD
Rand279
diabeticsw
ithNPD
R47ndash6
6yrMF
Ahvaz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersanddiabetic
retin
opathy
(P=0005)
T2DM
patie
ntsa
ndfoot
ulcer
Amolietal2011[109]
(i)VEG
Fminus7C
T(ii)V
EGFminus2578CA
247T2
DM
with
DFU
241
T2DM
with
outD
FUand
98healthy
43ndash6
4MF
Tehran
Case
control
ARM
S-PC
R
(i)Non
significantassociatio
nof
minus7C
Tcarrierswith
DFU
(ii)P
ositive
significant
associationbetweenAAcarriers
andDFU
(P=003)
SNPsin
glenu
cleotid
epo
lymorph
ismT
1DMtype1d
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4T2
DMtype2diabetes
mellitusP
CRp
olym
erasechainreactio
nRF
LPrestrictio
nfragmentlengthpo
lymorph
ismILinterle
ukinSS-PC
Rsequ
ence
specificP
CRV
DR
vitamin
DreceptorT
AP2
transpo
rter
2AT
P-bind
ingcassetteA
RMS-PC
Ram
plificatio
nrefractory
mutationsyste
mPC
RPC
R-SSPPC
Rsin
glespecificprim
erT
GF120573
transform
inggrow
thfactor120573D
Md
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4
MODY
maturity
onsetd
iabeteso
fthe
youn
gHNF-
1120572h
epatocytenu
clear
factor
1120572M
VCm
icrovascular
complicationsT
CF7L
2transcrip
tionfactor
7-lik
e2PC
R-SSCA
PCR
singlestr
andconformationpo
lymorph
ismanalysis
ER120572estr
ogen
receptor120572N
D
nond
iabeticsTC
totalcholesterolTG
trig
lycerid
esP
PAR-1205742peroxisomep
roliferator-activates
receptor120574G
LP-1R
glucagon
-like
peptid
1receptorAPO
apo
lipop
roteinC
XCL5chemokineC
-X-C
motifligand
5SD
F-1120573stro
malderiv
edfactor-1120573IRS
1amp2insulin
receptor
substrate1amp
2GSTglutathione-S-tr
ansfe
raseSLC
30A8solublecarrier3
0A8KC
NJPo
tassium
inwardly-rectify
ingchanneleN
OSendo
thelial
nitricoxidesynthaseVNTR
variablen
umbero
ftandem
repeatsEN
PP1ectoenzymen
ucleotidep
yrop
hosphateph
osph
odieste
rase1SU
MOsmallubiqu
itin-lik
emod
ifier4UCP
2un
coup
lingp
rotein
2MTH
FR
methylenetetrahydrofolateredu
ctaseIFN120574interferon120574C
CR5C-
Cchem
okiner
eceptortype5
INSR
insulin
receptorC
SGE
conformation-sensitive
gelelectroph
oresis
ACE
angiotensin
Icon
vertingenzyme
HFE
hem
ochrom
atosisgenePTP
N1proteintyrosin
Phosph
atase1B
CADcoron
arya
rteryd
iseaseCE
TPcho
leste
ryleste
rtransferp
roteinA
T1R
angiotensin
IreceptorMMP3
matrix
metalloproteinase
3CA
Scoronary
artery
steno
sisB
ChEK
Butyrylcho
linesteraseK
DNdiabetic
neph
ropathyAT
2Rang
iotensin
IIreceptorV
EGFvascularepith
elium
grow
thfactorD
Rdiabeticretin
opathy
PDR
proliferativ
ediabetic
retin
opathy
NPD
Rno
n-PD
RDFU
diabetic
foot
ulcer
Journal of Diabetes Research 13
321 T1DM Related Genes All the studies in this subgroupincluding 12 studies [22ndash33] were in a case control studydesign using PCR (polymerase chain reaction) [33] PCR-RFLP (restriction fragment length polymorphism) [22 2325 26 32] PCR-SSP (single specific primer) [24 28ndash32]and ARMS-PCR (amplification refractory mutation systemPCR) [27] method In all studies both men and women wereincluded and the overall 2519 subjects were under 40 yearsold
Association of interleukins including IL-18 (interleukin)and IL-12 with T1DM revealed that the minus137CG polymor-phism of IL-18 had significant association with T1DM (119875 =0037 119875 = 00001) while no significant relation was observedbetween minus607AC variant of this gene and T1DM [24 28]Investigating IL-12 also showed that there was a significantassociation between +1188AC polymorphism of this geneand T1DM (119875 = 0035) [30]
In 2 studies the association of +49AG variant of CTLA-4 (cytotoxic T lymphocyte associated antigen 4) was investi-gated and it was revealed that there was a positive significantassociation between AG genotype and T1DM (119875 = 001 119875 lt0001) [22 32] One of these studies also revealed that therewas a negative relation betweenAA genotype and T1DM [32]
Vitamin D receptor (VDR) was investigated in 2 studies[25 26] Both of them assessed the association of FokI BsmIApaI and TaqI variants of VDR with T1DM In one studywhichwas performed on 114 subjects Aa (119875 = 0003) FF (119875 =0008) and Bb (119875 = 0014) genotypes were shown to be pos-itively associated with T1DM but no significant associationwas observed between TaqI polymorphism and T1DM [25]Another study which was performed on 187 subjects showedno significant association between T1DM and FokI BsmIand ApaI However TT genotype was observed to be morefrequent in controls (119875 = 0007) and negatively associatedwith T1DM [26]
Different polymorphisms of TAP2 and their associationwith T1DM were investigated in 191 subjects It was shownthat Ile379Val and Stop687Gln had significant associationwith T1DM (119875 = 0001 and 119875 = 0013 resp) Other variantsof TAP2 (transporter 2 ATP-binding cassette) includingAla565Thr Arg651Cys and Ala665Thr were not associatedwith T1DM significantly [27]
Association of alleles A2ndashA9 of CD4 with T1DM wasassessed in 200 subjects It was revealed that A3 allele hadnegative (119875 = 0025) and A5 had positive (119875 = 0001)significant association with T1DM [33]
Association of some other genes including osteopontin(rs1126772 polymorphism) integrin 1205724 (rs1449263 polymor-phism) CD44 (rs8193 polymorphism) and TGF120573 (trans-forming growth factor) (+915CG polymorphism) was alsoinvestigated in 2 studies and no significant relation wasobserved between these variants and T1DM [23 29]
322 MODY In this category only one study was found [34]and the association of Val255Met polymorphism of HNF120572and diabetes was investigated in 101 subjects includingMODY subjects their relatives and healthy controls [34]Thestudy was designed as a case control association study andPCR-RFLP and direct sequencing was used for genotyping
of variants Val255Met mutation in this investigation wasobserved in MODY subjects and their relatives but not incontrol group
323 T2DM Related Genes In this subgroup 42 studieswere assessed and all of them were designed as case controlassociation studies [22 35ndash68 70ndash75] except for one whichwas cross sectionally designed [69] In 33 studies PCR- RFLPwas used for genotyping [22 36ndash38 40ndash54 56 58ndash61 63ndash66 69 72ndash75] In 5 of them PCR was used [35 57 62 70 71]and the remaining studies PCR-SCA [39] real-timePCR [55]ARMS-PCR [66] Gap PCR [67] and CSGE (conformation-sensitive gel electrophoresis) sequencing [68] as the genotyp-ing method were applied
Association between two polymorphisms of TCF7L2including rs7903146 (CT) and rs12255372 (GT)was assessedin three studies [38 48 53] In one study investigatingrs7903146 (CT) in 466 subjects significant difference in thefrequency of CC and CT genotypes was observed betweenT2DM and control group (119875 = 0045) [38] However inanother study this polymorphism showed a positive signifi-cant associationwith TT genotype in T2DM (119875 = 0008) [53]Investigation of rs12255372 (GT) polymorphism of TCF7L2in another study showed that among 491 subjects there wasa positive significant association between TT carriers andT2DM (119875 = 0014) [48]
Investigating the association of calreticulinwith T2DM in650 subjects showed two mutations only in case group 9 bpdeletion of 397ndash399 codons and GgtT mutation at IVSII-142[39]
Association of estrogen receptor 120572 and its PvuII(PPPppp) and XbaI(XXXxxx) polymorphism with T2DM intwo studies was assessed [40 49] In one study the significantassociation of PvuII and XbaI polymorphisms with T2DMwas observed (119875 = 0014 and 119875 = 0002 resp) [40] Inanother study it was revealed that pooled Pp+pp and XX+xxmale carriers have positive significant associationwithT2DM(119875 = 0001 and 119875 = 0026 resp) [49]
Association of Pro12Ala polymorphism of PPAR120574 withT2DMwas investigated in three studies [41 69 75] Negativesignificant association of AlaAla genotype with T2DM wasobserved in two studies (119875 = 0003) [41 75] AlaPro carrierswere shown to be positively associated in one study [41] andnegatively associated in another study [75] with T2DM (119875 lt0001 and 119875 = 0003 resp) However in the third studyno significant association was observed between Pro12Alapolymorphism of PPAR120574 and T2DM [69]
Association of different polymorphisms of ApoAI withT2DM was investigated in two studies [43 72] In one studyinvestigation of MSPI polymorphism showed no significantassociation with T2DM [43] In another study it was shownthat G-75A polymorphism of ApoAI was not associated withT2DM while a significant association was found betweenC+83T polymorphism and T2DM (119875 = 0028) [72]
Two studies assessed the association of minus156GgtC poly-morphism of CXCL5 with T2DM [44 65] In one studypositive significant association of GC carriers (119875 = 0006)and negative association of GG carriers (119875 = 001) was foundbetween diabetic patients and healthy controls [44] and
14 Journal of Diabetes Research
in another study positive significant association was foundbetween GC or CC carriers and T2DM (119875 = 0009) [64]
Adiponectin and its association with T2DM were inves-tigated in two studies [56 73] In one study two variantsincluding +45TG and minus11391GA were investigated but nosignificant relation was found between these two polymor-phisms and T2DM [56] However in another study investi-gating +45TG polymorphism of adiponectin it was revealedthat nonobese T2DM subjects had significantly higher TTgenotype (119875 = 004) [73]
In one study that investigated insulin receptor gene thefollowing mutations were found only in T2DM 511CgtA514TgtG 586 and 628TgtA on exon 2 694GgtC 680GgtA onexon 3 1627AgtT on exon 8 ATgtTG on intron 9 2007CgtCTon exon 9 2595CgtCT and 2669GgtCG on exon 13 2706 and2717CgtG 2752CgtT and 2753CgtG on exon 14 and 3471TgtAand 3516TgtG on exon 19 These mutations were not seen incontrol subjects [68]
Other variants which had significant association withT2DM included haptoglobin (allele 2-2) leptin (G-2548Apolymorphism) paraoxonase 2 (Ser311Cys polymorphism)GST (glutathione-S-transferase) M1 and GSTM1GSTT1interaction calpain-10 (SNP (single nucleotide polymor-phism) 43) IRS-1 (G972R polymorphism) and IRS-2(G1057D polymorphism) VDR (vitamin D receptor) (TaqIpolymorphism) KCNJ11 (E23K polymorphism) eNOS(endothelial nitric oxide synthase) VNTR (intron 4 ab pol-ymorphism) resistin (minus420CG polymorphism) and ACE(InsertionDeletion) [35ndash37 45 47 50 55 57 58 64 70]
In contrast to above variants CTLA4 (+49AG poly-morphism) HNF-1120572 (Ala98Val polymorphism) GLP-1R(glucagon-like peptid 1 receptor) (Thr149Met polymor-ohism) SLC30A8 (Arg325Trp polymorphism) GSTP1(Ile105Val polymorphism) glucokinase (minus30GA polymor-phism) SDF-1120573 (stromal derived factor -1 120573) (G801A poly-morphism) ApoE (apolipoprotein E) ENPP1 (ectoenzymenucleotide pyrophosphate phosphodiesterase 1) (K121Q poly-morphism) SUMO4 (small ubiquitin-like modifier 4)Met55Val polymorphism) MTHFR (C677T polymorphism)UCP2 (uncoupling protein 2) (minus866GA polymorphism)5HTTLPR IL-4 (minus590CT polymorphism) IFN-120574 (inter-feron 120574) (+874TA polymorphism) CCR5 (C-C chemokinereceptor type 5) (12057532mutation) HFE (hemochromatosisgene) (H63D C282Y PTPN1 (protein tyrosin Phosphatase1B)minus51delA minus451AgtG minus467TgtC minus1023CgtA minus1045GgtAminus1286 3 bp del ACA minus1291 9 bp del CTAGACTAA poly-morphisms) were not significantly associated with T2DM[22 42 46 50ndash52 54 59ndash63 66 67 71 74]
324 Genes Related to Insulin Resistance In this subgroupfour studies were assessed and all were designed as case-control association studies Three studies used PCR-RFL [7678 79] and one study used real-time PCR [77] for genotyping
The studies assessed in this subgroup showed a positiveassociation of TG carriers of +45TG polymorphism ofadiponectin (119875 = 0032) and Ala allele carriers of Pro12Alapolymorphism of PPAR120574 (119875 = 0036) with T2DM [76 77]A positive significant association of ff carriers of VDR wasalso shown (FokI polymorphism) (119875 = 002) and negative
association of 148insG carriers of PTPN1 (148insG polymor-phism) (119875 = 0041) with insulin resistance index [7879] However no significant association was shown betweenadiponectin receptor-2+795GA and T2DM [76]
325 Genes Related to Cardiovascular Disease in DiabetesDesign of all 11 studies in this subgroup was case-controlassociation study [80ndash84 86ndash90] except one study which wasdesigned as cross sectional [85] PCR-RFLP was used in all ofthem for genotyping [80ndash88 90] except in one study whichused ARMS-PCR method [89]
Paraoxonase 1 (163TA polymorphism) was the only vari-ant in this subgroup which was not significantly associatedwith atherosclerosis risk in T2DM [80] Investigation ofanother polymorphism of Paraoxonase 1 (Q192R) revealedthat diabetics with CAD had significant increase in RRgenotype (119875 lt 005) [81]
Investigating B1 and B2 alleles of CETP TaqI B allele in400 subjects showed that pooling of B1B1+B1B2 and B1B1genotypes had significant association with T2DM and CAD(119875 lt 001) On the other hand assessing the G894T poly-morphism of eNOS showed positive significant associationbetween TG and TT carriers and CAD (119875 lt 005) It was alsoshown that concomitant presence of NOS3 T allele and CEPTB1 allele was significantly associated with T2DM (119875 = 0004)and CAD (119875 = 0002) [83]
Investigation of apolipoprotein E (E2 E3 and E4) allelesshowed the association of E2 and E4 alleles with CAD(119875 lt 0001) [84 87] Also it was shown that interactionof butyrylcholinesterase (BChE K) and apolipoprotein E(ApoE) was associated significantly with CAD and diabetesApoE4BChE K had significant association with lipid profilesas well (119875 lt 005) [87]
Adiponectin +276GT and +45TG were significantlyassociated with CAD (119875 = 0023 and 0033 resp) [82] whileinvestigating minus1612 5A6A polymorphism of MMP-3 (matrixmetalloproteinase 3) showed a significant association withCAS (coronary artery stenosis) (119875 = 0008) [86]
In addition A1166C polymorphism of AT1R (angiotensinI receptor) and minus420CG polymorphism of resistin in dia-betic patients with CAD revealed significant association withdiabetes 119875 = 001 and 119875 = 0009 respectively [84 85]
Another study showed insertion(I)deletion(D) polymor-phismof angiotensin converting enzyme (ACE)DDgenotypewas significantly associated with higher blood pressure (119875 =0026) [89]
Factor V Leiden (G1691A polymorphism) prothrombin(G20210A polymorphism) and MTHFR (methylenetetrahy-drofolate reductase) (C677T polymorphism) were the vari-ants which were not significantly associated with CAD andT2DM in this subgroup [88]
326 Genes Related to Diabetic Nephropathy All of 15 studiesin this subgroup were designed as case-control associationstudies [91ndash106] In 7 studies PCR-RFLP was used forgenotyping [92ndash95 99 102 103] in four studies PCRwas used[98 101 104 105] and in 4 of them both PCR and PCR-RFLPwere used [91 96 97 100]
Journal of Diabetes Research 15
Studying the association of 163AG polymorphism ofSUMO4 showed a positive significant association betweenAA carriers and diabetic nephropathy (119875 lt 005) [93]
Studying the interaction of eNOS4ab and G894Trevealed positive significant association between 4a or 894Tallele carriers and macro- and microalbuminuria (119875 = 001119875 = 002 resp) [91] It was observed that the interaction ofeNOS (G894T polymorphism) andACE (ID alleles) was sig-nificantly associated with more frequent macroalbuminuria(119875 = 0035) [97]
It has also been shown that interaction of eNOS (G894Tpolymorphisms) and MTHFR (C677T and A1298C poly-morphisms) eNOS T1298 C and eNOS T677 T carriershad positive significant association with macroalbuminuriaIn addition significant association of eNOS GT+TT carrierswith lipid profile (119875 lt 005) was shown in this study [99]
C677T andA1298C polymorphisms ofMTHFRwere alsoinvestigated in another study revealing that 677T 1298Cand 677T1298C carriers were significantly associated withmacroalbuminuria (119875 lt 0001) Positive significant asso-ciation when pooling CT+TT genotypes and 677T1298Cwas also found with microalbuminuria (119875 lt 0001) [103]Investigating the interaction of MTHFR (A1298C C677Tpolymorphisms) and ACE (ID alleles) showed a positivesignificant association of ACE D677T (119875 = 0035) and ACED1298C (119875 = 0012) genotypeswithmacroalbuminuria [96]
ACE (ID alleles) polymorphisms were investigated inthree studies In one study positive significant association(119875 lt 001) between DD carriers and progression but notdevelopment of albuminuria was observed [104] In anotherstudy in nephropathic subjects association of DD carriersand T2DM (119875 = 0006) but not nephropathy was revealed[105] However another study did not show significant asso-ciation of ACE with macroalbuminuria [98] Interaction ofACE (ID alleles) with Factor V Leiden (G1691A polymor-phism) was not significant [100]
Association of interleukins including IL-4 and IL-10 withdiabetic nephropathy was also investigated in two studiesStudy of minus592CA polymorphism of IL-10 revealed positivesignificant association between CC carriers and nephropathy(119875 = 0001) [94] and study ofminus590CTpolymorphismof IL-4revealed positive significant association between CT carriersand nephropathy (119875 lt 0001) [101]
Other significant associations between variants and dia-betic nephropathy included AT2R (angiotensin II recep-tor) (minus1332GA polymorphism) VEGF (vascular epitheliumgrowth factor) (+405GC polymorphism) and VDR (TaqIpolymorphism) [92 95 102] ApaI polymorphism of VDRwas not significantly associated with diabetic nephropathy[102]
327 Genes Related to Diabetic Retinopathy All of the 3studies in this subgroup were conducted as case-controlassociation studies [106ndash108]
Investigating nullpositive genotype of GSTM1 in a studywhich used ARMS-PCR for genotyping revealed that nullgenotype is significantly associated with diabetic retinopathy(119875 lt 005) [106] This result was confirmed in another study
by using multiplex PCR as genotyping [107] although nosignificant association between GSTT1 and retinopathy wasfound in this study [107]
Investigating +405GC polymorphism of VEGF alsorevealed positive significant association between GG carriersand diabetic retinopathy (119875 = 0005) [108]
328 Genes Related to Diabetic Foot Ulcer In this subgrouponly one study was found [109] which was case-controldesigned and used ARMS-PCR for genotyping In this studyassociation of minus7CT and minus2578CA polymorphisms ofVEGF with diabetic foot ulcer (DFU) was investigated and apositive significant association betweenAA carriers andDFU(119875 = 003) was observed But no significant association wasfound between minus7CT of VEGF and DFU [109]
4 Discussion
Diabetes mellitus is the eighth most frequent disease leadingcause of death throughout the world and now ranks the fifthfollowing communicable diseases cardiovascular diseasecancer and injuries [110] Prevalence of diabetes mellitus isincreasing worldwide [6]
Type 2 diabetes is the most frequent type of diabetesmellitus [110 111] Multiple genes and environmental factorsaffect the prevalence of T2DM Systematic review and meta-analysis studies have assessed the association between dif-ferent genes and T2DM Glutathione-S-transferase includingGSTMI GSTM1 and GSTP1 are important genes and theirassociation with diabetes has been investigated in two meta-analysis studies [112 113] It was revealed that null genotypeof both GSTM1 and GSTT1 could be as a risk factor fordiabetes while no significant association was found betweenGSTP1 and diabetes [112 113] These results are in linewith our finding and confirming the association of the nullgenotype of GSTT1 and GSTM1 with T2DM in Iranianpopulation [50] The relation between GSTT1 and GSTM1and diabetic retinopathy has also been shown in Iranianpopulation [106 107]
MTHFR is another important gene in association withT2DM and other related complications No associationof C677T polymorphism of MTHFR gene was found inAfricans Asians and Caucasians [114] MTHFR is a genewhich is involved in DNA methylation and synthesis andregulated folate activity It has been reported that mutanthomozygote and heterozygote of C677T polymorphism ofMTHFR increase plasma homocysteine which is an impor-tant factor leading to diabetic nephropathy (DN) and as aresult C677T polymorphism of MTHFR can be associatedwith the development of DN In Caucasians this associationhas also been observed [115] In Iranian population in linewith other populations no significant association was foundbetween MTHFR polymorphisms and T2DM [63] althoughsignificant association of 677T and 1298C alleles with diabeticnephropathy was observed [87] Interaction of two polymor-phisms and also interaction of MTHFR polymorphisms withother genes such as ACE and eNOS showed an associationwith development of DN [96 99]
16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Journal of Diabetes Research 9
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
T2DM
patie
ntsa
ndinsulin
resistance
Nam
varanetal2012
[76]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin
receptor-2+795G
A
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTG
carriersandT2
DM
(P=0032)
(ii)N
onsig
nificantassociatio
nbetween+7
94GA
carriersand
insulin
resistance
Nam
varanetal2011[77]
PPAR120574
Pro12Ala
101T
2DM
and128healthy
30ndash70y
rMF
Shira
zCa
secontrol
Realtim
ePCR
Positives
ignificantassociatio
nbetweenAlaallelecarriersand
T2DM
(P=0036)
Hossein-nezhadetal2009
[78]
VDRFokI
(FFFfff
)105T2
DM55plusmn10yrM
FTehran
Case
serie
sPC
R-RF
LPPo
sitives
ignificantassociatio
nbetweenffcarriersandinsulin
resistanceind
ex(P
=002)
Moo
sapo
oretal2007
[79]
PTPN
1148insG
71T2
DM
and264ND
20ndash80y
rMF
Tehran
Case
control
PCR-RF
LP
Negatives
ignificantassociatio
nbetween148insGcarriersand
insulin
resistanceind
ex(119875=0041)
T2DM
patie
ntsa
ndheartd
iseases
Bayatm
akoo
etal2013
[80]
Paraoxon
ase116
3TA
(L55M)
105CA
DD
Mand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPNon
significance
Bayatm
akoo
etal2012
[81]
Paraoxon
ase1575Ggt
A(Q
192R
)105DMCADand95
CADN
D
lt85
yrM
FTabriz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenRR
carriersand
CADD
M(Plt005)
Estegh
amatietal2012
[82]
(i)Ad
ipon
ectin
+45TG
(ii)A
dipo
nectin+276G
T114
CADD
Mand127DM
42ndash71yrMF
Tehran
Case
control
PCR-RF
LP
(i)Negatives
ignificant
associationbetween45TT
carriersandCA
D(P
=0033)
(ii)P
ositive
significant
associationbetween276G
GcarriersandCA
D(P
=0023)
Rahimietal2012
[83]
eNOSG8
94T
CETP
B1
102CA
DD
M105
CADN
D101
DMand
92ND45ndash66
yrM
FKe
rmanshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
concom
itant
presence
ofNOS3
TalleleandCE
PTB1
allelewith
T2DM
(P=000
4)andCA
D(119875=0002)
Assalietal2011[84]
AT1RA116
6C145CA
DD
Mand164CA
D
lt50
andge50
yrM
FMashh
adCa
secontrol
PCR-RF
LPPo
sitives
ignificantassociatio
nof
ACandCC
carrierswith
DM
(119875=001)
Emam
gholipou
retal2009
[85]
Resistin
minus420C
G113CA
Dwith
andwith
outD
M
58plusmn9yrM
FTehran
Crosssectio
nal
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDM
(119875=0009)
10 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Fallahetal2010
[86]
MMP-3minus1612
5A6A
305CA
DD
Mand313DM
61plusmn9yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetween6A
6AcarriersandCA
S(P
=0008)
Vaisi-Raygani
etal2010
[87]
BChE
KG1
615A
APO
EE2
E3E4
118DM162
CADN
D172
DMCADand
179healthy
42ndash6
8yrMF
Kerm
anshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GAA
Aand
E4carrierswith
CADandDM
(Plt005)
Positives
ignificantassociatio
nof
BChE
KAp
oE4carrierswith
CADand
DM
(Plt005)
Sign
ificant
associationof
BChE
KAp
oE4with
lipid
profi
le(119875lt005)
Rahimietal2009
[88]
Factor
VLeidenG
1691A
Prothrom
binG2
0210A
MTH
FRC677T
65CA
DD
M52CA
DN
Dand
59healthy46
064y
rMF
Kerm
anshah
Case
control
PCR-RF
LPNon
significance
Nakhjavanietal2007
[89]
ACEID
82DM
with
hypertensio
nand87
DM
with
outh
ypertension
49ndash6
3yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
hypertensio
n(P
=0026)
Vaisi-Raygani
etal2007
[90]
Apolipop
roteinE2E3
E4
152CA
DD
M262
CADN
D
and300healthy35ndash73y
rMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nof
E2andE4
allelec
arrie
rswith
CAD(Plt0001)
T2DM
patie
ntsa
ndneph
ropathy
Rahimietal2013
[91]
eNOS4abG
894T
63T2
DMm
icroalbu
minuria
57T2
DMm
acroalbu
minuria
52T2
DMnormoalbum
inuria
121D
Nand
101h
ealth
y45ndash6
6yrMF
Kerm
anshah
Case
control
PCR
PCR-RF
LP
Positives
ignificantassociatio
nof
4aor
894T
allelecarriersand
macro-(P=001)o
rmicroalbu
minuria(P
=002)
Rahimietal2013
[92]
AT2R
minus1332GA
28T2
DMm
icroalbu
minuria
22T2
DMm
acroalbu
minuria
20T2
DMnormoalbum
inuria
and112healthy43ndash6
3yrMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(P
=0016)
Shahsavare
tal2013
[93]
SUMO4163A
G(M
55V)
50T2
DD
Nand50
T2DM
non-DN25ndash45
yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(Plt005)
Arababadi
etal2012
[94]
IL-10minus592C
A100T2
DMnon
-DN100
T2DMD
Nand100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDN
(119875=0001)
Journal of Diabetes Research 11
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2012
[95]
VEG
F+4
05G
C255T2
DMm
icroalbu
minuria
and235T2
DMnon
albu
minuric
50ndash6
7yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersand
albu
minuria(P
=0002)
Rahimietal2012
[96]
MTH
FRA1298C
C677T
ACEID
72T2
DMM
icAlb
68T2
DMM
acAlband72
T2DMnon
-DN46ndash
65yrM
FKe
rmanshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nof
ACED677T(P
=0035)
and
ACED12
98C(P
=0012)
carrierswith
macroalbu
minuria
Rahimietal2012
[97]
eNOSG8
94T
ACEID
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nbetweenAC
EDcarriersand
macroalbu
minuria(P
=0035)
Feleh
garietal2011[98]
ACEID
68T2
DMm
acroalbu
minuria
and72
T2Dmnormoalbum
inuria
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR
Non
significance
Jafarietal2011[99]
eNOSG8
94T
MTH
FRC677TA
1298C
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
eNOST1298
CandeN
OS
T677Tcarrierswith
macroalbu
minuria(Plt005)
(ii)S
ignificantassociatio
nof
eNOSGT+
TTcarrierswith
lipid
profi
le(Plt005)
Rahimietal2011[100]
ACEID
Factor
VLeidenG
1691A
217mean55both
Kerm
anshah
Case
control
PCR
PCR-RF
LPNon
significance
Arababadi2010[101]
IL-4minus590C
T100T2
DMD
Nand150healthy
33ndash4
7yrMF
Rafsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenCT
carriersandDN
(119875lt0001)
Nosratabadi
etal2010
[102]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DMnon
-DN100
T2DMD
Nand
100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandDN
(119875=0012)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandDN
Rahimietal2010
[103]
MTH
FRC677TA
1298C
72T2
DMm
icrolbum
iunira
68T2
DMm
acroalbu
minuria
and72
T2DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
677T1298C
and677T
1298C
carrierswith
macroalbu
minoria
(Plt0001)
(ii)P
ositive
significant
associationof
CT+T
Tand
677T
1298Ccarrierswith
microalbu
minuria(Plt0001)
12 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2009
[104]
ACEID
129T
2DMm
icrolbum
iunira
48T2
DMm
acroalbu
minuria
and145T
2DMnormoalbum
inuria
594plusmn85y
rMF
Tehran
Crosssectio
nal
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
progressionof
albu
minuria
(119875lt001)b
utno
tits
developm
ent
Nikzamiretal2006
[105]
ACEID
85T2
DMD
N85T2
DMnon
-DN
and91
healthy37ndash6
7yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(119875=0006)b
utno
tDN
T2DM
patie
ntsa
ndretin
opathy
Abbasietal2013
[106]
GST
M1n
ullp
ositive
80DRand80
healthy
30ndash70y
rMF
Rasht
Case
control
ARM
S-PC
RNullgenotypes
ignificant
association
Plt005
Dadbinp
oure
tal2013
[107]
(i)GST
M1n
ullp
ositive
(ii)G
STT1nullp
ositive
57DRand58
non-DR
35ndash6
5yrMF
Yazd
Case
control
Multip
lexPC
R
(i)Nullgenotypeo
fGST
M1o
rGST
T1sig
nificantassociatio
n(119875=004)
(ii)N
onsig
nificantassociatio
nof
GST
T1nu
llcarrierswith
DR
Fegh
hietal2011[108]
VEG
F+4
05G
C119
diabeticsw
ithPD
Rand279
diabeticsw
ithNPD
R47ndash6
6yrMF
Ahvaz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersanddiabetic
retin
opathy
(P=0005)
T2DM
patie
ntsa
ndfoot
ulcer
Amolietal2011[109]
(i)VEG
Fminus7C
T(ii)V
EGFminus2578CA
247T2
DM
with
DFU
241
T2DM
with
outD
FUand
98healthy
43ndash6
4MF
Tehran
Case
control
ARM
S-PC
R
(i)Non
significantassociatio
nof
minus7C
Tcarrierswith
DFU
(ii)P
ositive
significant
associationbetweenAAcarriers
andDFU
(P=003)
SNPsin
glenu
cleotid
epo
lymorph
ismT
1DMtype1d
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4T2
DMtype2diabetes
mellitusP
CRp
olym
erasechainreactio
nRF
LPrestrictio
nfragmentlengthpo
lymorph
ismILinterle
ukinSS-PC
Rsequ
ence
specificP
CRV
DR
vitamin
DreceptorT
AP2
transpo
rter
2AT
P-bind
ingcassetteA
RMS-PC
Ram
plificatio
nrefractory
mutationsyste
mPC
RPC
R-SSPPC
Rsin
glespecificprim
erT
GF120573
transform
inggrow
thfactor120573D
Md
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4
MODY
maturity
onsetd
iabeteso
fthe
youn
gHNF-
1120572h
epatocytenu
clear
factor
1120572M
VCm
icrovascular
complicationsT
CF7L
2transcrip
tionfactor
7-lik
e2PC
R-SSCA
PCR
singlestr
andconformationpo
lymorph
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ER120572estr
ogen
receptor120572N
D
nond
iabeticsTC
totalcholesterolTG
trig
lycerid
esP
PAR-1205742peroxisomep
roliferator-activates
receptor120574G
LP-1R
glucagon
-like
peptid
1receptorAPO
apo
lipop
roteinC
XCL5chemokineC
-X-C
motifligand
5SD
F-1120573stro
malderiv
edfactor-1120573IRS
1amp2insulin
receptor
substrate1amp
2GSTglutathione-S-tr
ansfe
raseSLC
30A8solublecarrier3
0A8KC
NJPo
tassium
inwardly-rectify
ingchanneleN
OSendo
thelial
nitricoxidesynthaseVNTR
variablen
umbero
ftandem
repeatsEN
PP1ectoenzymen
ucleotidep
yrop
hosphateph
osph
odieste
rase1SU
MOsmallubiqu
itin-lik
emod
ifier4UCP
2un
coup
lingp
rotein
2MTH
FR
methylenetetrahydrofolateredu
ctaseIFN120574interferon120574C
CR5C-
Cchem
okiner
eceptortype5
INSR
insulin
receptorC
SGE
conformation-sensitive
gelelectroph
oresis
ACE
angiotensin
Icon
vertingenzyme
HFE
hem
ochrom
atosisgenePTP
N1proteintyrosin
Phosph
atase1B
CADcoron
arya
rteryd
iseaseCE
TPcho
leste
ryleste
rtransferp
roteinA
T1R
angiotensin
IreceptorMMP3
matrix
metalloproteinase
3CA
Scoronary
artery
steno
sisB
ChEK
Butyrylcho
linesteraseK
DNdiabetic
neph
ropathyAT
2Rang
iotensin
IIreceptorV
EGFvascularepith
elium
grow
thfactorD
Rdiabeticretin
opathy
PDR
proliferativ
ediabetic
retin
opathy
NPD
Rno
n-PD
RDFU
diabetic
foot
ulcer
Journal of Diabetes Research 13
321 T1DM Related Genes All the studies in this subgroupincluding 12 studies [22ndash33] were in a case control studydesign using PCR (polymerase chain reaction) [33] PCR-RFLP (restriction fragment length polymorphism) [22 2325 26 32] PCR-SSP (single specific primer) [24 28ndash32]and ARMS-PCR (amplification refractory mutation systemPCR) [27] method In all studies both men and women wereincluded and the overall 2519 subjects were under 40 yearsold
Association of interleukins including IL-18 (interleukin)and IL-12 with T1DM revealed that the minus137CG polymor-phism of IL-18 had significant association with T1DM (119875 =0037 119875 = 00001) while no significant relation was observedbetween minus607AC variant of this gene and T1DM [24 28]Investigating IL-12 also showed that there was a significantassociation between +1188AC polymorphism of this geneand T1DM (119875 = 0035) [30]
In 2 studies the association of +49AG variant of CTLA-4 (cytotoxic T lymphocyte associated antigen 4) was investi-gated and it was revealed that there was a positive significantassociation between AG genotype and T1DM (119875 = 001 119875 lt0001) [22 32] One of these studies also revealed that therewas a negative relation betweenAA genotype and T1DM [32]
Vitamin D receptor (VDR) was investigated in 2 studies[25 26] Both of them assessed the association of FokI BsmIApaI and TaqI variants of VDR with T1DM In one studywhichwas performed on 114 subjects Aa (119875 = 0003) FF (119875 =0008) and Bb (119875 = 0014) genotypes were shown to be pos-itively associated with T1DM but no significant associationwas observed between TaqI polymorphism and T1DM [25]Another study which was performed on 187 subjects showedno significant association between T1DM and FokI BsmIand ApaI However TT genotype was observed to be morefrequent in controls (119875 = 0007) and negatively associatedwith T1DM [26]
Different polymorphisms of TAP2 and their associationwith T1DM were investigated in 191 subjects It was shownthat Ile379Val and Stop687Gln had significant associationwith T1DM (119875 = 0001 and 119875 = 0013 resp) Other variantsof TAP2 (transporter 2 ATP-binding cassette) includingAla565Thr Arg651Cys and Ala665Thr were not associatedwith T1DM significantly [27]
Association of alleles A2ndashA9 of CD4 with T1DM wasassessed in 200 subjects It was revealed that A3 allele hadnegative (119875 = 0025) and A5 had positive (119875 = 0001)significant association with T1DM [33]
Association of some other genes including osteopontin(rs1126772 polymorphism) integrin 1205724 (rs1449263 polymor-phism) CD44 (rs8193 polymorphism) and TGF120573 (trans-forming growth factor) (+915CG polymorphism) was alsoinvestigated in 2 studies and no significant relation wasobserved between these variants and T1DM [23 29]
322 MODY In this category only one study was found [34]and the association of Val255Met polymorphism of HNF120572and diabetes was investigated in 101 subjects includingMODY subjects their relatives and healthy controls [34]Thestudy was designed as a case control association study andPCR-RFLP and direct sequencing was used for genotyping
of variants Val255Met mutation in this investigation wasobserved in MODY subjects and their relatives but not incontrol group
323 T2DM Related Genes In this subgroup 42 studieswere assessed and all of them were designed as case controlassociation studies [22 35ndash68 70ndash75] except for one whichwas cross sectionally designed [69] In 33 studies PCR- RFLPwas used for genotyping [22 36ndash38 40ndash54 56 58ndash61 63ndash66 69 72ndash75] In 5 of them PCR was used [35 57 62 70 71]and the remaining studies PCR-SCA [39] real-timePCR [55]ARMS-PCR [66] Gap PCR [67] and CSGE (conformation-sensitive gel electrophoresis) sequencing [68] as the genotyp-ing method were applied
Association between two polymorphisms of TCF7L2including rs7903146 (CT) and rs12255372 (GT)was assessedin three studies [38 48 53] In one study investigatingrs7903146 (CT) in 466 subjects significant difference in thefrequency of CC and CT genotypes was observed betweenT2DM and control group (119875 = 0045) [38] However inanother study this polymorphism showed a positive signifi-cant associationwith TT genotype in T2DM (119875 = 0008) [53]Investigation of rs12255372 (GT) polymorphism of TCF7L2in another study showed that among 491 subjects there wasa positive significant association between TT carriers andT2DM (119875 = 0014) [48]
Investigating the association of calreticulinwith T2DM in650 subjects showed two mutations only in case group 9 bpdeletion of 397ndash399 codons and GgtT mutation at IVSII-142[39]
Association of estrogen receptor 120572 and its PvuII(PPPppp) and XbaI(XXXxxx) polymorphism with T2DM intwo studies was assessed [40 49] In one study the significantassociation of PvuII and XbaI polymorphisms with T2DMwas observed (119875 = 0014 and 119875 = 0002 resp) [40] Inanother study it was revealed that pooled Pp+pp and XX+xxmale carriers have positive significant associationwithT2DM(119875 = 0001 and 119875 = 0026 resp) [49]
Association of Pro12Ala polymorphism of PPAR120574 withT2DMwas investigated in three studies [41 69 75] Negativesignificant association of AlaAla genotype with T2DM wasobserved in two studies (119875 = 0003) [41 75] AlaPro carrierswere shown to be positively associated in one study [41] andnegatively associated in another study [75] with T2DM (119875 lt0001 and 119875 = 0003 resp) However in the third studyno significant association was observed between Pro12Alapolymorphism of PPAR120574 and T2DM [69]
Association of different polymorphisms of ApoAI withT2DM was investigated in two studies [43 72] In one studyinvestigation of MSPI polymorphism showed no significantassociation with T2DM [43] In another study it was shownthat G-75A polymorphism of ApoAI was not associated withT2DM while a significant association was found betweenC+83T polymorphism and T2DM (119875 = 0028) [72]
Two studies assessed the association of minus156GgtC poly-morphism of CXCL5 with T2DM [44 65] In one studypositive significant association of GC carriers (119875 = 0006)and negative association of GG carriers (119875 = 001) was foundbetween diabetic patients and healthy controls [44] and
14 Journal of Diabetes Research
in another study positive significant association was foundbetween GC or CC carriers and T2DM (119875 = 0009) [64]
Adiponectin and its association with T2DM were inves-tigated in two studies [56 73] In one study two variantsincluding +45TG and minus11391GA were investigated but nosignificant relation was found between these two polymor-phisms and T2DM [56] However in another study investi-gating +45TG polymorphism of adiponectin it was revealedthat nonobese T2DM subjects had significantly higher TTgenotype (119875 = 004) [73]
In one study that investigated insulin receptor gene thefollowing mutations were found only in T2DM 511CgtA514TgtG 586 and 628TgtA on exon 2 694GgtC 680GgtA onexon 3 1627AgtT on exon 8 ATgtTG on intron 9 2007CgtCTon exon 9 2595CgtCT and 2669GgtCG on exon 13 2706 and2717CgtG 2752CgtT and 2753CgtG on exon 14 and 3471TgtAand 3516TgtG on exon 19 These mutations were not seen incontrol subjects [68]
Other variants which had significant association withT2DM included haptoglobin (allele 2-2) leptin (G-2548Apolymorphism) paraoxonase 2 (Ser311Cys polymorphism)GST (glutathione-S-transferase) M1 and GSTM1GSTT1interaction calpain-10 (SNP (single nucleotide polymor-phism) 43) IRS-1 (G972R polymorphism) and IRS-2(G1057D polymorphism) VDR (vitamin D receptor) (TaqIpolymorphism) KCNJ11 (E23K polymorphism) eNOS(endothelial nitric oxide synthase) VNTR (intron 4 ab pol-ymorphism) resistin (minus420CG polymorphism) and ACE(InsertionDeletion) [35ndash37 45 47 50 55 57 58 64 70]
In contrast to above variants CTLA4 (+49AG poly-morphism) HNF-1120572 (Ala98Val polymorphism) GLP-1R(glucagon-like peptid 1 receptor) (Thr149Met polymor-ohism) SLC30A8 (Arg325Trp polymorphism) GSTP1(Ile105Val polymorphism) glucokinase (minus30GA polymor-phism) SDF-1120573 (stromal derived factor -1 120573) (G801A poly-morphism) ApoE (apolipoprotein E) ENPP1 (ectoenzymenucleotide pyrophosphate phosphodiesterase 1) (K121Q poly-morphism) SUMO4 (small ubiquitin-like modifier 4)Met55Val polymorphism) MTHFR (C677T polymorphism)UCP2 (uncoupling protein 2) (minus866GA polymorphism)5HTTLPR IL-4 (minus590CT polymorphism) IFN-120574 (inter-feron 120574) (+874TA polymorphism) CCR5 (C-C chemokinereceptor type 5) (12057532mutation) HFE (hemochromatosisgene) (H63D C282Y PTPN1 (protein tyrosin Phosphatase1B)minus51delA minus451AgtG minus467TgtC minus1023CgtA minus1045GgtAminus1286 3 bp del ACA minus1291 9 bp del CTAGACTAA poly-morphisms) were not significantly associated with T2DM[22 42 46 50ndash52 54 59ndash63 66 67 71 74]
324 Genes Related to Insulin Resistance In this subgroupfour studies were assessed and all were designed as case-control association studies Three studies used PCR-RFL [7678 79] and one study used real-time PCR [77] for genotyping
The studies assessed in this subgroup showed a positiveassociation of TG carriers of +45TG polymorphism ofadiponectin (119875 = 0032) and Ala allele carriers of Pro12Alapolymorphism of PPAR120574 (119875 = 0036) with T2DM [76 77]A positive significant association of ff carriers of VDR wasalso shown (FokI polymorphism) (119875 = 002) and negative
association of 148insG carriers of PTPN1 (148insG polymor-phism) (119875 = 0041) with insulin resistance index [7879] However no significant association was shown betweenadiponectin receptor-2+795GA and T2DM [76]
325 Genes Related to Cardiovascular Disease in DiabetesDesign of all 11 studies in this subgroup was case-controlassociation study [80ndash84 86ndash90] except one study which wasdesigned as cross sectional [85] PCR-RFLP was used in all ofthem for genotyping [80ndash88 90] except in one study whichused ARMS-PCR method [89]
Paraoxonase 1 (163TA polymorphism) was the only vari-ant in this subgroup which was not significantly associatedwith atherosclerosis risk in T2DM [80] Investigation ofanother polymorphism of Paraoxonase 1 (Q192R) revealedthat diabetics with CAD had significant increase in RRgenotype (119875 lt 005) [81]
Investigating B1 and B2 alleles of CETP TaqI B allele in400 subjects showed that pooling of B1B1+B1B2 and B1B1genotypes had significant association with T2DM and CAD(119875 lt 001) On the other hand assessing the G894T poly-morphism of eNOS showed positive significant associationbetween TG and TT carriers and CAD (119875 lt 005) It was alsoshown that concomitant presence of NOS3 T allele and CEPTB1 allele was significantly associated with T2DM (119875 = 0004)and CAD (119875 = 0002) [83]
Investigation of apolipoprotein E (E2 E3 and E4) allelesshowed the association of E2 and E4 alleles with CAD(119875 lt 0001) [84 87] Also it was shown that interactionof butyrylcholinesterase (BChE K) and apolipoprotein E(ApoE) was associated significantly with CAD and diabetesApoE4BChE K had significant association with lipid profilesas well (119875 lt 005) [87]
Adiponectin +276GT and +45TG were significantlyassociated with CAD (119875 = 0023 and 0033 resp) [82] whileinvestigating minus1612 5A6A polymorphism of MMP-3 (matrixmetalloproteinase 3) showed a significant association withCAS (coronary artery stenosis) (119875 = 0008) [86]
In addition A1166C polymorphism of AT1R (angiotensinI receptor) and minus420CG polymorphism of resistin in dia-betic patients with CAD revealed significant association withdiabetes 119875 = 001 and 119875 = 0009 respectively [84 85]
Another study showed insertion(I)deletion(D) polymor-phismof angiotensin converting enzyme (ACE)DDgenotypewas significantly associated with higher blood pressure (119875 =0026) [89]
Factor V Leiden (G1691A polymorphism) prothrombin(G20210A polymorphism) and MTHFR (methylenetetrahy-drofolate reductase) (C677T polymorphism) were the vari-ants which were not significantly associated with CAD andT2DM in this subgroup [88]
326 Genes Related to Diabetic Nephropathy All of 15 studiesin this subgroup were designed as case-control associationstudies [91ndash106] In 7 studies PCR-RFLP was used forgenotyping [92ndash95 99 102 103] in four studies PCRwas used[98 101 104 105] and in 4 of them both PCR and PCR-RFLPwere used [91 96 97 100]
Journal of Diabetes Research 15
Studying the association of 163AG polymorphism ofSUMO4 showed a positive significant association betweenAA carriers and diabetic nephropathy (119875 lt 005) [93]
Studying the interaction of eNOS4ab and G894Trevealed positive significant association between 4a or 894Tallele carriers and macro- and microalbuminuria (119875 = 001119875 = 002 resp) [91] It was observed that the interaction ofeNOS (G894T polymorphism) andACE (ID alleles) was sig-nificantly associated with more frequent macroalbuminuria(119875 = 0035) [97]
It has also been shown that interaction of eNOS (G894Tpolymorphisms) and MTHFR (C677T and A1298C poly-morphisms) eNOS T1298 C and eNOS T677 T carriershad positive significant association with macroalbuminuriaIn addition significant association of eNOS GT+TT carrierswith lipid profile (119875 lt 005) was shown in this study [99]
C677T andA1298C polymorphisms ofMTHFRwere alsoinvestigated in another study revealing that 677T 1298Cand 677T1298C carriers were significantly associated withmacroalbuminuria (119875 lt 0001) Positive significant asso-ciation when pooling CT+TT genotypes and 677T1298Cwas also found with microalbuminuria (119875 lt 0001) [103]Investigating the interaction of MTHFR (A1298C C677Tpolymorphisms) and ACE (ID alleles) showed a positivesignificant association of ACE D677T (119875 = 0035) and ACED1298C (119875 = 0012) genotypeswithmacroalbuminuria [96]
ACE (ID alleles) polymorphisms were investigated inthree studies In one study positive significant association(119875 lt 001) between DD carriers and progression but notdevelopment of albuminuria was observed [104] In anotherstudy in nephropathic subjects association of DD carriersand T2DM (119875 = 0006) but not nephropathy was revealed[105] However another study did not show significant asso-ciation of ACE with macroalbuminuria [98] Interaction ofACE (ID alleles) with Factor V Leiden (G1691A polymor-phism) was not significant [100]
Association of interleukins including IL-4 and IL-10 withdiabetic nephropathy was also investigated in two studiesStudy of minus592CA polymorphism of IL-10 revealed positivesignificant association between CC carriers and nephropathy(119875 = 0001) [94] and study ofminus590CTpolymorphismof IL-4revealed positive significant association between CT carriersand nephropathy (119875 lt 0001) [101]
Other significant associations between variants and dia-betic nephropathy included AT2R (angiotensin II recep-tor) (minus1332GA polymorphism) VEGF (vascular epitheliumgrowth factor) (+405GC polymorphism) and VDR (TaqIpolymorphism) [92 95 102] ApaI polymorphism of VDRwas not significantly associated with diabetic nephropathy[102]
327 Genes Related to Diabetic Retinopathy All of the 3studies in this subgroup were conducted as case-controlassociation studies [106ndash108]
Investigating nullpositive genotype of GSTM1 in a studywhich used ARMS-PCR for genotyping revealed that nullgenotype is significantly associated with diabetic retinopathy(119875 lt 005) [106] This result was confirmed in another study
by using multiplex PCR as genotyping [107] although nosignificant association between GSTT1 and retinopathy wasfound in this study [107]
Investigating +405GC polymorphism of VEGF alsorevealed positive significant association between GG carriersand diabetic retinopathy (119875 = 0005) [108]
328 Genes Related to Diabetic Foot Ulcer In this subgrouponly one study was found [109] which was case-controldesigned and used ARMS-PCR for genotyping In this studyassociation of minus7CT and minus2578CA polymorphisms ofVEGF with diabetic foot ulcer (DFU) was investigated and apositive significant association betweenAA carriers andDFU(119875 = 003) was observed But no significant association wasfound between minus7CT of VEGF and DFU [109]
4 Discussion
Diabetes mellitus is the eighth most frequent disease leadingcause of death throughout the world and now ranks the fifthfollowing communicable diseases cardiovascular diseasecancer and injuries [110] Prevalence of diabetes mellitus isincreasing worldwide [6]
Type 2 diabetes is the most frequent type of diabetesmellitus [110 111] Multiple genes and environmental factorsaffect the prevalence of T2DM Systematic review and meta-analysis studies have assessed the association between dif-ferent genes and T2DM Glutathione-S-transferase includingGSTMI GSTM1 and GSTP1 are important genes and theirassociation with diabetes has been investigated in two meta-analysis studies [112 113] It was revealed that null genotypeof both GSTM1 and GSTT1 could be as a risk factor fordiabetes while no significant association was found betweenGSTP1 and diabetes [112 113] These results are in linewith our finding and confirming the association of the nullgenotype of GSTT1 and GSTM1 with T2DM in Iranianpopulation [50] The relation between GSTT1 and GSTM1and diabetic retinopathy has also been shown in Iranianpopulation [106 107]
MTHFR is another important gene in association withT2DM and other related complications No associationof C677T polymorphism of MTHFR gene was found inAfricans Asians and Caucasians [114] MTHFR is a genewhich is involved in DNA methylation and synthesis andregulated folate activity It has been reported that mutanthomozygote and heterozygote of C677T polymorphism ofMTHFR increase plasma homocysteine which is an impor-tant factor leading to diabetic nephropathy (DN) and as aresult C677T polymorphism of MTHFR can be associatedwith the development of DN In Caucasians this associationhas also been observed [115] In Iranian population in linewith other populations no significant association was foundbetween MTHFR polymorphisms and T2DM [63] althoughsignificant association of 677T and 1298C alleles with diabeticnephropathy was observed [87] Interaction of two polymor-phisms and also interaction of MTHFR polymorphisms withother genes such as ACE and eNOS showed an associationwith development of DN [96 99]
16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
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Disease Markers
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OncologyJournal of
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
10 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Fallahetal2010
[86]
MMP-3minus1612
5A6A
305CA
DD
Mand313DM
61plusmn9yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetween6A
6AcarriersandCA
S(P
=0008)
Vaisi-Raygani
etal2010
[87]
BChE
KG1
615A
APO
EE2
E3E4
118DM162
CADN
D172
DMCADand
179healthy
42ndash6
8yrMF
Kerm
anshah
Case
control
PCR-RF
LP
Positives
ignificantassociatio
nof
GAA
Aand
E4carrierswith
CADandDM
(Plt005)
Positives
ignificantassociatio
nof
BChE
KAp
oE4carrierswith
CADand
DM
(Plt005)
Sign
ificant
associationof
BChE
KAp
oE4with
lipid
profi
le(119875lt005)
Rahimietal2009
[88]
Factor
VLeidenG
1691A
Prothrom
binG2
0210A
MTH
FRC677T
65CA
DD
M52CA
DN
Dand
59healthy46
064y
rMF
Kerm
anshah
Case
control
PCR-RF
LPNon
significance
Nakhjavanietal2007
[89]
ACEID
82DM
with
hypertensio
nand87
DM
with
outh
ypertension
49ndash6
3yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
hypertensio
n(P
=0026)
Vaisi-Raygani
etal2007
[90]
Apolipop
roteinE2E3
E4
152CA
DD
M262
CADN
D
and300healthy35ndash73y
rMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nof
E2andE4
allelec
arrie
rswith
CAD(Plt0001)
T2DM
patie
ntsa
ndneph
ropathy
Rahimietal2013
[91]
eNOS4abG
894T
63T2
DMm
icroalbu
minuria
57T2
DMm
acroalbu
minuria
52T2
DMnormoalbum
inuria
121D
Nand
101h
ealth
y45ndash6
6yrMF
Kerm
anshah
Case
control
PCR
PCR-RF
LP
Positives
ignificantassociatio
nof
4aor
894T
allelecarriersand
macro-(P=001)o
rmicroalbu
minuria(P
=002)
Rahimietal2013
[92]
AT2R
minus1332GA
28T2
DMm
icroalbu
minuria
22T2
DMm
acroalbu
minuria
20T2
DMnormoalbum
inuria
and112healthy43ndash6
3yrMF
Kerm
anshah
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(P
=0016)
Shahsavare
tal2013
[93]
SUMO4163A
G(M
55V)
50T2
DD
Nand50
T2DM
non-DN25ndash45
yrM
FTehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenAAcarriersand
neph
ropathy(Plt005)
Arababadi
etal2012
[94]
IL-10minus592C
A100T2
DMnon
-DN100
T2DMD
Nand100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenCC
carriersandDN
(119875=0001)
Journal of Diabetes Research 11
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2012
[95]
VEG
F+4
05G
C255T2
DMm
icroalbu
minuria
and235T2
DMnon
albu
minuric
50ndash6
7yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersand
albu
minuria(P
=0002)
Rahimietal2012
[96]
MTH
FRA1298C
C677T
ACEID
72T2
DMM
icAlb
68T2
DMM
acAlband72
T2DMnon
-DN46ndash
65yrM
FKe
rmanshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nof
ACED677T(P
=0035)
and
ACED12
98C(P
=0012)
carrierswith
macroalbu
minuria
Rahimietal2012
[97]
eNOSG8
94T
ACEID
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nbetweenAC
EDcarriersand
macroalbu
minuria(P
=0035)
Feleh
garietal2011[98]
ACEID
68T2
DMm
acroalbu
minuria
and72
T2Dmnormoalbum
inuria
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR
Non
significance
Jafarietal2011[99]
eNOSG8
94T
MTH
FRC677TA
1298C
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
eNOST1298
CandeN
OS
T677Tcarrierswith
macroalbu
minuria(Plt005)
(ii)S
ignificantassociatio
nof
eNOSGT+
TTcarrierswith
lipid
profi
le(Plt005)
Rahimietal2011[100]
ACEID
Factor
VLeidenG
1691A
217mean55both
Kerm
anshah
Case
control
PCR
PCR-RF
LPNon
significance
Arababadi2010[101]
IL-4minus590C
T100T2
DMD
Nand150healthy
33ndash4
7yrMF
Rafsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenCT
carriersandDN
(119875lt0001)
Nosratabadi
etal2010
[102]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DMnon
-DN100
T2DMD
Nand
100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandDN
(119875=0012)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandDN
Rahimietal2010
[103]
MTH
FRC677TA
1298C
72T2
DMm
icrolbum
iunira
68T2
DMm
acroalbu
minuria
and72
T2DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
677T1298C
and677T
1298C
carrierswith
macroalbu
minoria
(Plt0001)
(ii)P
ositive
significant
associationof
CT+T
Tand
677T
1298Ccarrierswith
microalbu
minuria(Plt0001)
12 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2009
[104]
ACEID
129T
2DMm
icrolbum
iunira
48T2
DMm
acroalbu
minuria
and145T
2DMnormoalbum
inuria
594plusmn85y
rMF
Tehran
Crosssectio
nal
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
progressionof
albu
minuria
(119875lt001)b
utno
tits
developm
ent
Nikzamiretal2006
[105]
ACEID
85T2
DMD
N85T2
DMnon
-DN
and91
healthy37ndash6
7yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(119875=0006)b
utno
tDN
T2DM
patie
ntsa
ndretin
opathy
Abbasietal2013
[106]
GST
M1n
ullp
ositive
80DRand80
healthy
30ndash70y
rMF
Rasht
Case
control
ARM
S-PC
RNullgenotypes
ignificant
association
Plt005
Dadbinp
oure
tal2013
[107]
(i)GST
M1n
ullp
ositive
(ii)G
STT1nullp
ositive
57DRand58
non-DR
35ndash6
5yrMF
Yazd
Case
control
Multip
lexPC
R
(i)Nullgenotypeo
fGST
M1o
rGST
T1sig
nificantassociatio
n(119875=004)
(ii)N
onsig
nificantassociatio
nof
GST
T1nu
llcarrierswith
DR
Fegh
hietal2011[108]
VEG
F+4
05G
C119
diabeticsw
ithPD
Rand279
diabeticsw
ithNPD
R47ndash6
6yrMF
Ahvaz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersanddiabetic
retin
opathy
(P=0005)
T2DM
patie
ntsa
ndfoot
ulcer
Amolietal2011[109]
(i)VEG
Fminus7C
T(ii)V
EGFminus2578CA
247T2
DM
with
DFU
241
T2DM
with
outD
FUand
98healthy
43ndash6
4MF
Tehran
Case
control
ARM
S-PC
R
(i)Non
significantassociatio
nof
minus7C
Tcarrierswith
DFU
(ii)P
ositive
significant
associationbetweenAAcarriers
andDFU
(P=003)
SNPsin
glenu
cleotid
epo
lymorph
ismT
1DMtype1d
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4T2
DMtype2diabetes
mellitusP
CRp
olym
erasechainreactio
nRF
LPrestrictio
nfragmentlengthpo
lymorph
ismILinterle
ukinSS-PC
Rsequ
ence
specificP
CRV
DR
vitamin
DreceptorT
AP2
transpo
rter
2AT
P-bind
ingcassetteA
RMS-PC
Ram
plificatio
nrefractory
mutationsyste
mPC
RPC
R-SSPPC
Rsin
glespecificprim
erT
GF120573
transform
inggrow
thfactor120573D
Md
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4
MODY
maturity
onsetd
iabeteso
fthe
youn
gHNF-
1120572h
epatocytenu
clear
factor
1120572M
VCm
icrovascular
complicationsT
CF7L
2transcrip
tionfactor
7-lik
e2PC
R-SSCA
PCR
singlestr
andconformationpo
lymorph
ismanalysis
ER120572estr
ogen
receptor120572N
D
nond
iabeticsTC
totalcholesterolTG
trig
lycerid
esP
PAR-1205742peroxisomep
roliferator-activates
receptor120574G
LP-1R
glucagon
-like
peptid
1receptorAPO
apo
lipop
roteinC
XCL5chemokineC
-X-C
motifligand
5SD
F-1120573stro
malderiv
edfactor-1120573IRS
1amp2insulin
receptor
substrate1amp
2GSTglutathione-S-tr
ansfe
raseSLC
30A8solublecarrier3
0A8KC
NJPo
tassium
inwardly-rectify
ingchanneleN
OSendo
thelial
nitricoxidesynthaseVNTR
variablen
umbero
ftandem
repeatsEN
PP1ectoenzymen
ucleotidep
yrop
hosphateph
osph
odieste
rase1SU
MOsmallubiqu
itin-lik
emod
ifier4UCP
2un
coup
lingp
rotein
2MTH
FR
methylenetetrahydrofolateredu
ctaseIFN120574interferon120574C
CR5C-
Cchem
okiner
eceptortype5
INSR
insulin
receptorC
SGE
conformation-sensitive
gelelectroph
oresis
ACE
angiotensin
Icon
vertingenzyme
HFE
hem
ochrom
atosisgenePTP
N1proteintyrosin
Phosph
atase1B
CADcoron
arya
rteryd
iseaseCE
TPcho
leste
ryleste
rtransferp
roteinA
T1R
angiotensin
IreceptorMMP3
matrix
metalloproteinase
3CA
Scoronary
artery
steno
sisB
ChEK
Butyrylcho
linesteraseK
DNdiabetic
neph
ropathyAT
2Rang
iotensin
IIreceptorV
EGFvascularepith
elium
grow
thfactorD
Rdiabeticretin
opathy
PDR
proliferativ
ediabetic
retin
opathy
NPD
Rno
n-PD
RDFU
diabetic
foot
ulcer
Journal of Diabetes Research 13
321 T1DM Related Genes All the studies in this subgroupincluding 12 studies [22ndash33] were in a case control studydesign using PCR (polymerase chain reaction) [33] PCR-RFLP (restriction fragment length polymorphism) [22 2325 26 32] PCR-SSP (single specific primer) [24 28ndash32]and ARMS-PCR (amplification refractory mutation systemPCR) [27] method In all studies both men and women wereincluded and the overall 2519 subjects were under 40 yearsold
Association of interleukins including IL-18 (interleukin)and IL-12 with T1DM revealed that the minus137CG polymor-phism of IL-18 had significant association with T1DM (119875 =0037 119875 = 00001) while no significant relation was observedbetween minus607AC variant of this gene and T1DM [24 28]Investigating IL-12 also showed that there was a significantassociation between +1188AC polymorphism of this geneand T1DM (119875 = 0035) [30]
In 2 studies the association of +49AG variant of CTLA-4 (cytotoxic T lymphocyte associated antigen 4) was investi-gated and it was revealed that there was a positive significantassociation between AG genotype and T1DM (119875 = 001 119875 lt0001) [22 32] One of these studies also revealed that therewas a negative relation betweenAA genotype and T1DM [32]
Vitamin D receptor (VDR) was investigated in 2 studies[25 26] Both of them assessed the association of FokI BsmIApaI and TaqI variants of VDR with T1DM In one studywhichwas performed on 114 subjects Aa (119875 = 0003) FF (119875 =0008) and Bb (119875 = 0014) genotypes were shown to be pos-itively associated with T1DM but no significant associationwas observed between TaqI polymorphism and T1DM [25]Another study which was performed on 187 subjects showedno significant association between T1DM and FokI BsmIand ApaI However TT genotype was observed to be morefrequent in controls (119875 = 0007) and negatively associatedwith T1DM [26]
Different polymorphisms of TAP2 and their associationwith T1DM were investigated in 191 subjects It was shownthat Ile379Val and Stop687Gln had significant associationwith T1DM (119875 = 0001 and 119875 = 0013 resp) Other variantsof TAP2 (transporter 2 ATP-binding cassette) includingAla565Thr Arg651Cys and Ala665Thr were not associatedwith T1DM significantly [27]
Association of alleles A2ndashA9 of CD4 with T1DM wasassessed in 200 subjects It was revealed that A3 allele hadnegative (119875 = 0025) and A5 had positive (119875 = 0001)significant association with T1DM [33]
Association of some other genes including osteopontin(rs1126772 polymorphism) integrin 1205724 (rs1449263 polymor-phism) CD44 (rs8193 polymorphism) and TGF120573 (trans-forming growth factor) (+915CG polymorphism) was alsoinvestigated in 2 studies and no significant relation wasobserved between these variants and T1DM [23 29]
322 MODY In this category only one study was found [34]and the association of Val255Met polymorphism of HNF120572and diabetes was investigated in 101 subjects includingMODY subjects their relatives and healthy controls [34]Thestudy was designed as a case control association study andPCR-RFLP and direct sequencing was used for genotyping
of variants Val255Met mutation in this investigation wasobserved in MODY subjects and their relatives but not incontrol group
323 T2DM Related Genes In this subgroup 42 studieswere assessed and all of them were designed as case controlassociation studies [22 35ndash68 70ndash75] except for one whichwas cross sectionally designed [69] In 33 studies PCR- RFLPwas used for genotyping [22 36ndash38 40ndash54 56 58ndash61 63ndash66 69 72ndash75] In 5 of them PCR was used [35 57 62 70 71]and the remaining studies PCR-SCA [39] real-timePCR [55]ARMS-PCR [66] Gap PCR [67] and CSGE (conformation-sensitive gel electrophoresis) sequencing [68] as the genotyp-ing method were applied
Association between two polymorphisms of TCF7L2including rs7903146 (CT) and rs12255372 (GT)was assessedin three studies [38 48 53] In one study investigatingrs7903146 (CT) in 466 subjects significant difference in thefrequency of CC and CT genotypes was observed betweenT2DM and control group (119875 = 0045) [38] However inanother study this polymorphism showed a positive signifi-cant associationwith TT genotype in T2DM (119875 = 0008) [53]Investigation of rs12255372 (GT) polymorphism of TCF7L2in another study showed that among 491 subjects there wasa positive significant association between TT carriers andT2DM (119875 = 0014) [48]
Investigating the association of calreticulinwith T2DM in650 subjects showed two mutations only in case group 9 bpdeletion of 397ndash399 codons and GgtT mutation at IVSII-142[39]
Association of estrogen receptor 120572 and its PvuII(PPPppp) and XbaI(XXXxxx) polymorphism with T2DM intwo studies was assessed [40 49] In one study the significantassociation of PvuII and XbaI polymorphisms with T2DMwas observed (119875 = 0014 and 119875 = 0002 resp) [40] Inanother study it was revealed that pooled Pp+pp and XX+xxmale carriers have positive significant associationwithT2DM(119875 = 0001 and 119875 = 0026 resp) [49]
Association of Pro12Ala polymorphism of PPAR120574 withT2DMwas investigated in three studies [41 69 75] Negativesignificant association of AlaAla genotype with T2DM wasobserved in two studies (119875 = 0003) [41 75] AlaPro carrierswere shown to be positively associated in one study [41] andnegatively associated in another study [75] with T2DM (119875 lt0001 and 119875 = 0003 resp) However in the third studyno significant association was observed between Pro12Alapolymorphism of PPAR120574 and T2DM [69]
Association of different polymorphisms of ApoAI withT2DM was investigated in two studies [43 72] In one studyinvestigation of MSPI polymorphism showed no significantassociation with T2DM [43] In another study it was shownthat G-75A polymorphism of ApoAI was not associated withT2DM while a significant association was found betweenC+83T polymorphism and T2DM (119875 = 0028) [72]
Two studies assessed the association of minus156GgtC poly-morphism of CXCL5 with T2DM [44 65] In one studypositive significant association of GC carriers (119875 = 0006)and negative association of GG carriers (119875 = 001) was foundbetween diabetic patients and healthy controls [44] and
14 Journal of Diabetes Research
in another study positive significant association was foundbetween GC or CC carriers and T2DM (119875 = 0009) [64]
Adiponectin and its association with T2DM were inves-tigated in two studies [56 73] In one study two variantsincluding +45TG and minus11391GA were investigated but nosignificant relation was found between these two polymor-phisms and T2DM [56] However in another study investi-gating +45TG polymorphism of adiponectin it was revealedthat nonobese T2DM subjects had significantly higher TTgenotype (119875 = 004) [73]
In one study that investigated insulin receptor gene thefollowing mutations were found only in T2DM 511CgtA514TgtG 586 and 628TgtA on exon 2 694GgtC 680GgtA onexon 3 1627AgtT on exon 8 ATgtTG on intron 9 2007CgtCTon exon 9 2595CgtCT and 2669GgtCG on exon 13 2706 and2717CgtG 2752CgtT and 2753CgtG on exon 14 and 3471TgtAand 3516TgtG on exon 19 These mutations were not seen incontrol subjects [68]
Other variants which had significant association withT2DM included haptoglobin (allele 2-2) leptin (G-2548Apolymorphism) paraoxonase 2 (Ser311Cys polymorphism)GST (glutathione-S-transferase) M1 and GSTM1GSTT1interaction calpain-10 (SNP (single nucleotide polymor-phism) 43) IRS-1 (G972R polymorphism) and IRS-2(G1057D polymorphism) VDR (vitamin D receptor) (TaqIpolymorphism) KCNJ11 (E23K polymorphism) eNOS(endothelial nitric oxide synthase) VNTR (intron 4 ab pol-ymorphism) resistin (minus420CG polymorphism) and ACE(InsertionDeletion) [35ndash37 45 47 50 55 57 58 64 70]
In contrast to above variants CTLA4 (+49AG poly-morphism) HNF-1120572 (Ala98Val polymorphism) GLP-1R(glucagon-like peptid 1 receptor) (Thr149Met polymor-ohism) SLC30A8 (Arg325Trp polymorphism) GSTP1(Ile105Val polymorphism) glucokinase (minus30GA polymor-phism) SDF-1120573 (stromal derived factor -1 120573) (G801A poly-morphism) ApoE (apolipoprotein E) ENPP1 (ectoenzymenucleotide pyrophosphate phosphodiesterase 1) (K121Q poly-morphism) SUMO4 (small ubiquitin-like modifier 4)Met55Val polymorphism) MTHFR (C677T polymorphism)UCP2 (uncoupling protein 2) (minus866GA polymorphism)5HTTLPR IL-4 (minus590CT polymorphism) IFN-120574 (inter-feron 120574) (+874TA polymorphism) CCR5 (C-C chemokinereceptor type 5) (12057532mutation) HFE (hemochromatosisgene) (H63D C282Y PTPN1 (protein tyrosin Phosphatase1B)minus51delA minus451AgtG minus467TgtC minus1023CgtA minus1045GgtAminus1286 3 bp del ACA minus1291 9 bp del CTAGACTAA poly-morphisms) were not significantly associated with T2DM[22 42 46 50ndash52 54 59ndash63 66 67 71 74]
324 Genes Related to Insulin Resistance In this subgroupfour studies were assessed and all were designed as case-control association studies Three studies used PCR-RFL [7678 79] and one study used real-time PCR [77] for genotyping
The studies assessed in this subgroup showed a positiveassociation of TG carriers of +45TG polymorphism ofadiponectin (119875 = 0032) and Ala allele carriers of Pro12Alapolymorphism of PPAR120574 (119875 = 0036) with T2DM [76 77]A positive significant association of ff carriers of VDR wasalso shown (FokI polymorphism) (119875 = 002) and negative
association of 148insG carriers of PTPN1 (148insG polymor-phism) (119875 = 0041) with insulin resistance index [7879] However no significant association was shown betweenadiponectin receptor-2+795GA and T2DM [76]
325 Genes Related to Cardiovascular Disease in DiabetesDesign of all 11 studies in this subgroup was case-controlassociation study [80ndash84 86ndash90] except one study which wasdesigned as cross sectional [85] PCR-RFLP was used in all ofthem for genotyping [80ndash88 90] except in one study whichused ARMS-PCR method [89]
Paraoxonase 1 (163TA polymorphism) was the only vari-ant in this subgroup which was not significantly associatedwith atherosclerosis risk in T2DM [80] Investigation ofanother polymorphism of Paraoxonase 1 (Q192R) revealedthat diabetics with CAD had significant increase in RRgenotype (119875 lt 005) [81]
Investigating B1 and B2 alleles of CETP TaqI B allele in400 subjects showed that pooling of B1B1+B1B2 and B1B1genotypes had significant association with T2DM and CAD(119875 lt 001) On the other hand assessing the G894T poly-morphism of eNOS showed positive significant associationbetween TG and TT carriers and CAD (119875 lt 005) It was alsoshown that concomitant presence of NOS3 T allele and CEPTB1 allele was significantly associated with T2DM (119875 = 0004)and CAD (119875 = 0002) [83]
Investigation of apolipoprotein E (E2 E3 and E4) allelesshowed the association of E2 and E4 alleles with CAD(119875 lt 0001) [84 87] Also it was shown that interactionof butyrylcholinesterase (BChE K) and apolipoprotein E(ApoE) was associated significantly with CAD and diabetesApoE4BChE K had significant association with lipid profilesas well (119875 lt 005) [87]
Adiponectin +276GT and +45TG were significantlyassociated with CAD (119875 = 0023 and 0033 resp) [82] whileinvestigating minus1612 5A6A polymorphism of MMP-3 (matrixmetalloproteinase 3) showed a significant association withCAS (coronary artery stenosis) (119875 = 0008) [86]
In addition A1166C polymorphism of AT1R (angiotensinI receptor) and minus420CG polymorphism of resistin in dia-betic patients with CAD revealed significant association withdiabetes 119875 = 001 and 119875 = 0009 respectively [84 85]
Another study showed insertion(I)deletion(D) polymor-phismof angiotensin converting enzyme (ACE)DDgenotypewas significantly associated with higher blood pressure (119875 =0026) [89]
Factor V Leiden (G1691A polymorphism) prothrombin(G20210A polymorphism) and MTHFR (methylenetetrahy-drofolate reductase) (C677T polymorphism) were the vari-ants which were not significantly associated with CAD andT2DM in this subgroup [88]
326 Genes Related to Diabetic Nephropathy All of 15 studiesin this subgroup were designed as case-control associationstudies [91ndash106] In 7 studies PCR-RFLP was used forgenotyping [92ndash95 99 102 103] in four studies PCRwas used[98 101 104 105] and in 4 of them both PCR and PCR-RFLPwere used [91 96 97 100]
Journal of Diabetes Research 15
Studying the association of 163AG polymorphism ofSUMO4 showed a positive significant association betweenAA carriers and diabetic nephropathy (119875 lt 005) [93]
Studying the interaction of eNOS4ab and G894Trevealed positive significant association between 4a or 894Tallele carriers and macro- and microalbuminuria (119875 = 001119875 = 002 resp) [91] It was observed that the interaction ofeNOS (G894T polymorphism) andACE (ID alleles) was sig-nificantly associated with more frequent macroalbuminuria(119875 = 0035) [97]
It has also been shown that interaction of eNOS (G894Tpolymorphisms) and MTHFR (C677T and A1298C poly-morphisms) eNOS T1298 C and eNOS T677 T carriershad positive significant association with macroalbuminuriaIn addition significant association of eNOS GT+TT carrierswith lipid profile (119875 lt 005) was shown in this study [99]
C677T andA1298C polymorphisms ofMTHFRwere alsoinvestigated in another study revealing that 677T 1298Cand 677T1298C carriers were significantly associated withmacroalbuminuria (119875 lt 0001) Positive significant asso-ciation when pooling CT+TT genotypes and 677T1298Cwas also found with microalbuminuria (119875 lt 0001) [103]Investigating the interaction of MTHFR (A1298C C677Tpolymorphisms) and ACE (ID alleles) showed a positivesignificant association of ACE D677T (119875 = 0035) and ACED1298C (119875 = 0012) genotypeswithmacroalbuminuria [96]
ACE (ID alleles) polymorphisms were investigated inthree studies In one study positive significant association(119875 lt 001) between DD carriers and progression but notdevelopment of albuminuria was observed [104] In anotherstudy in nephropathic subjects association of DD carriersand T2DM (119875 = 0006) but not nephropathy was revealed[105] However another study did not show significant asso-ciation of ACE with macroalbuminuria [98] Interaction ofACE (ID alleles) with Factor V Leiden (G1691A polymor-phism) was not significant [100]
Association of interleukins including IL-4 and IL-10 withdiabetic nephropathy was also investigated in two studiesStudy of minus592CA polymorphism of IL-10 revealed positivesignificant association between CC carriers and nephropathy(119875 = 0001) [94] and study ofminus590CTpolymorphismof IL-4revealed positive significant association between CT carriersand nephropathy (119875 lt 0001) [101]
Other significant associations between variants and dia-betic nephropathy included AT2R (angiotensin II recep-tor) (minus1332GA polymorphism) VEGF (vascular epitheliumgrowth factor) (+405GC polymorphism) and VDR (TaqIpolymorphism) [92 95 102] ApaI polymorphism of VDRwas not significantly associated with diabetic nephropathy[102]
327 Genes Related to Diabetic Retinopathy All of the 3studies in this subgroup were conducted as case-controlassociation studies [106ndash108]
Investigating nullpositive genotype of GSTM1 in a studywhich used ARMS-PCR for genotyping revealed that nullgenotype is significantly associated with diabetic retinopathy(119875 lt 005) [106] This result was confirmed in another study
by using multiplex PCR as genotyping [107] although nosignificant association between GSTT1 and retinopathy wasfound in this study [107]
Investigating +405GC polymorphism of VEGF alsorevealed positive significant association between GG carriersand diabetic retinopathy (119875 = 0005) [108]
328 Genes Related to Diabetic Foot Ulcer In this subgrouponly one study was found [109] which was case-controldesigned and used ARMS-PCR for genotyping In this studyassociation of minus7CT and minus2578CA polymorphisms ofVEGF with diabetic foot ulcer (DFU) was investigated and apositive significant association betweenAA carriers andDFU(119875 = 003) was observed But no significant association wasfound between minus7CT of VEGF and DFU [109]
4 Discussion
Diabetes mellitus is the eighth most frequent disease leadingcause of death throughout the world and now ranks the fifthfollowing communicable diseases cardiovascular diseasecancer and injuries [110] Prevalence of diabetes mellitus isincreasing worldwide [6]
Type 2 diabetes is the most frequent type of diabetesmellitus [110 111] Multiple genes and environmental factorsaffect the prevalence of T2DM Systematic review and meta-analysis studies have assessed the association between dif-ferent genes and T2DM Glutathione-S-transferase includingGSTMI GSTM1 and GSTP1 are important genes and theirassociation with diabetes has been investigated in two meta-analysis studies [112 113] It was revealed that null genotypeof both GSTM1 and GSTT1 could be as a risk factor fordiabetes while no significant association was found betweenGSTP1 and diabetes [112 113] These results are in linewith our finding and confirming the association of the nullgenotype of GSTT1 and GSTM1 with T2DM in Iranianpopulation [50] The relation between GSTT1 and GSTM1and diabetic retinopathy has also been shown in Iranianpopulation [106 107]
MTHFR is another important gene in association withT2DM and other related complications No associationof C677T polymorphism of MTHFR gene was found inAfricans Asians and Caucasians [114] MTHFR is a genewhich is involved in DNA methylation and synthesis andregulated folate activity It has been reported that mutanthomozygote and heterozygote of C677T polymorphism ofMTHFR increase plasma homocysteine which is an impor-tant factor leading to diabetic nephropathy (DN) and as aresult C677T polymorphism of MTHFR can be associatedwith the development of DN In Caucasians this associationhas also been observed [115] In Iranian population in linewith other populations no significant association was foundbetween MTHFR polymorphisms and T2DM [63] althoughsignificant association of 677T and 1298C alleles with diabeticnephropathy was observed [87] Interaction of two polymor-phisms and also interaction of MTHFR polymorphisms withother genes such as ACE and eNOS showed an associationwith development of DN [96 99]
16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Journal of Diabetes Research 11
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2012
[95]
VEG
F+4
05G
C255T2
DMm
icroalbu
minuria
and235T2
DMnon
albu
minuric
50ndash6
7yrMF
Tehran
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersand
albu
minuria(P
=0002)
Rahimietal2012
[96]
MTH
FRA1298C
C677T
ACEID
72T2
DMM
icAlb
68T2
DMM
acAlband72
T2DMnon
-DN46ndash
65yrM
FKe
rmanshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nof
ACED677T(P
=0035)
and
ACED12
98C(P
=0012)
carrierswith
macroalbu
minuria
Rahimietal2012
[97]
eNOSG8
94T
ACEID
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LPPC
R
Positives
ignificantassociatio
nbetweenAC
EDcarriersand
macroalbu
minuria(P
=0035)
Feleh
garietal2011[98]
ACEID
68T2
DMm
acroalbu
minuria
and72
T2Dmnormoalbum
inuria
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR
Non
significance
Jafarietal2011[99]
eNOSG8
94T
MTH
FRC677TA
1298C
72T2
DMm
icroalbu
minuria
68T2
DMm
acroalbu
minuriaand
72T2
DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
eNOST1298
CandeN
OS
T677Tcarrierswith
macroalbu
minuria(Plt005)
(ii)S
ignificantassociatio
nof
eNOSGT+
TTcarrierswith
lipid
profi
le(Plt005)
Rahimietal2011[100]
ACEID
Factor
VLeidenG
1691A
217mean55both
Kerm
anshah
Case
control
PCR
PCR-RF
LPNon
significance
Arababadi2010[101]
IL-4minus590C
T100T2
DMD
Nand150healthy
33ndash4
7yrMF
Rafsanjan
Case
control
PCR
Positives
ignificantassociatio
nbetweenCT
carriersandDN
(119875lt0001)
Nosratabadi
etal2010
[102]
(i)VDRTaqI
(TTTttt)
(ii)V
DRAp
aI(A
AAa
aa)
100T2
DMnon
-DN100
T2DMD
Nand
100healthy
31ndash4
9yrMF
Rafsanjan
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nbetweenTt
carriersandDN
(119875=0012)
(ii)N
onsig
nificantassociatio
nbetweenAp
aIcarriersandDN
Rahimietal2010
[103]
MTH
FRC677TA
1298C
72T2
DMm
icrolbum
iunira
68T2
DMm
acroalbu
minuria
and72
T2DMnon
-DN
46ndash6
5yrMF
Kerm
anshah
Case
control
PCR-RF
LP
(i)Po
sitives
ignificantassociatio
nof
677T1298C
and677T
1298C
carrierswith
macroalbu
minoria
(Plt0001)
(ii)P
ositive
significant
associationof
CT+T
Tand
677T
1298Ccarrierswith
microalbu
minuria(Plt0001)
12 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2009
[104]
ACEID
129T
2DMm
icrolbum
iunira
48T2
DMm
acroalbu
minuria
and145T
2DMnormoalbum
inuria
594plusmn85y
rMF
Tehran
Crosssectio
nal
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
progressionof
albu
minuria
(119875lt001)b
utno
tits
developm
ent
Nikzamiretal2006
[105]
ACEID
85T2
DMD
N85T2
DMnon
-DN
and91
healthy37ndash6
7yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(119875=0006)b
utno
tDN
T2DM
patie
ntsa
ndretin
opathy
Abbasietal2013
[106]
GST
M1n
ullp
ositive
80DRand80
healthy
30ndash70y
rMF
Rasht
Case
control
ARM
S-PC
RNullgenotypes
ignificant
association
Plt005
Dadbinp
oure
tal2013
[107]
(i)GST
M1n
ullp
ositive
(ii)G
STT1nullp
ositive
57DRand58
non-DR
35ndash6
5yrMF
Yazd
Case
control
Multip
lexPC
R
(i)Nullgenotypeo
fGST
M1o
rGST
T1sig
nificantassociatio
n(119875=004)
(ii)N
onsig
nificantassociatio
nof
GST
T1nu
llcarrierswith
DR
Fegh
hietal2011[108]
VEG
F+4
05G
C119
diabeticsw
ithPD
Rand279
diabeticsw
ithNPD
R47ndash6
6yrMF
Ahvaz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersanddiabetic
retin
opathy
(P=0005)
T2DM
patie
ntsa
ndfoot
ulcer
Amolietal2011[109]
(i)VEG
Fminus7C
T(ii)V
EGFminus2578CA
247T2
DM
with
DFU
241
T2DM
with
outD
FUand
98healthy
43ndash6
4MF
Tehran
Case
control
ARM
S-PC
R
(i)Non
significantassociatio
nof
minus7C
Tcarrierswith
DFU
(ii)P
ositive
significant
associationbetweenAAcarriers
andDFU
(P=003)
SNPsin
glenu
cleotid
epo
lymorph
ismT
1DMtype1d
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4T2
DMtype2diabetes
mellitusP
CRp
olym
erasechainreactio
nRF
LPrestrictio
nfragmentlengthpo
lymorph
ismILinterle
ukinSS-PC
Rsequ
ence
specificP
CRV
DR
vitamin
DreceptorT
AP2
transpo
rter
2AT
P-bind
ingcassetteA
RMS-PC
Ram
plificatio
nrefractory
mutationsyste
mPC
RPC
R-SSPPC
Rsin
glespecificprim
erT
GF120573
transform
inggrow
thfactor120573D
Md
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4
MODY
maturity
onsetd
iabeteso
fthe
youn
gHNF-
1120572h
epatocytenu
clear
factor
1120572M
VCm
icrovascular
complicationsT
CF7L
2transcrip
tionfactor
7-lik
e2PC
R-SSCA
PCR
singlestr
andconformationpo
lymorph
ismanalysis
ER120572estr
ogen
receptor120572N
D
nond
iabeticsTC
totalcholesterolTG
trig
lycerid
esP
PAR-1205742peroxisomep
roliferator-activates
receptor120574G
LP-1R
glucagon
-like
peptid
1receptorAPO
apo
lipop
roteinC
XCL5chemokineC
-X-C
motifligand
5SD
F-1120573stro
malderiv
edfactor-1120573IRS
1amp2insulin
receptor
substrate1amp
2GSTglutathione-S-tr
ansfe
raseSLC
30A8solublecarrier3
0A8KC
NJPo
tassium
inwardly-rectify
ingchanneleN
OSendo
thelial
nitricoxidesynthaseVNTR
variablen
umbero
ftandem
repeatsEN
PP1ectoenzymen
ucleotidep
yrop
hosphateph
osph
odieste
rase1SU
MOsmallubiqu
itin-lik
emod
ifier4UCP
2un
coup
lingp
rotein
2MTH
FR
methylenetetrahydrofolateredu
ctaseIFN120574interferon120574C
CR5C-
Cchem
okiner
eceptortype5
INSR
insulin
receptorC
SGE
conformation-sensitive
gelelectroph
oresis
ACE
angiotensin
Icon
vertingenzyme
HFE
hem
ochrom
atosisgenePTP
N1proteintyrosin
Phosph
atase1B
CADcoron
arya
rteryd
iseaseCE
TPcho
leste
ryleste
rtransferp
roteinA
T1R
angiotensin
IreceptorMMP3
matrix
metalloproteinase
3CA
Scoronary
artery
steno
sisB
ChEK
Butyrylcho
linesteraseK
DNdiabetic
neph
ropathyAT
2Rang
iotensin
IIreceptorV
EGFvascularepith
elium
grow
thfactorD
Rdiabeticretin
opathy
PDR
proliferativ
ediabetic
retin
opathy
NPD
Rno
n-PD
RDFU
diabetic
foot
ulcer
Journal of Diabetes Research 13
321 T1DM Related Genes All the studies in this subgroupincluding 12 studies [22ndash33] were in a case control studydesign using PCR (polymerase chain reaction) [33] PCR-RFLP (restriction fragment length polymorphism) [22 2325 26 32] PCR-SSP (single specific primer) [24 28ndash32]and ARMS-PCR (amplification refractory mutation systemPCR) [27] method In all studies both men and women wereincluded and the overall 2519 subjects were under 40 yearsold
Association of interleukins including IL-18 (interleukin)and IL-12 with T1DM revealed that the minus137CG polymor-phism of IL-18 had significant association with T1DM (119875 =0037 119875 = 00001) while no significant relation was observedbetween minus607AC variant of this gene and T1DM [24 28]Investigating IL-12 also showed that there was a significantassociation between +1188AC polymorphism of this geneand T1DM (119875 = 0035) [30]
In 2 studies the association of +49AG variant of CTLA-4 (cytotoxic T lymphocyte associated antigen 4) was investi-gated and it was revealed that there was a positive significantassociation between AG genotype and T1DM (119875 = 001 119875 lt0001) [22 32] One of these studies also revealed that therewas a negative relation betweenAA genotype and T1DM [32]
Vitamin D receptor (VDR) was investigated in 2 studies[25 26] Both of them assessed the association of FokI BsmIApaI and TaqI variants of VDR with T1DM In one studywhichwas performed on 114 subjects Aa (119875 = 0003) FF (119875 =0008) and Bb (119875 = 0014) genotypes were shown to be pos-itively associated with T1DM but no significant associationwas observed between TaqI polymorphism and T1DM [25]Another study which was performed on 187 subjects showedno significant association between T1DM and FokI BsmIand ApaI However TT genotype was observed to be morefrequent in controls (119875 = 0007) and negatively associatedwith T1DM [26]
Different polymorphisms of TAP2 and their associationwith T1DM were investigated in 191 subjects It was shownthat Ile379Val and Stop687Gln had significant associationwith T1DM (119875 = 0001 and 119875 = 0013 resp) Other variantsof TAP2 (transporter 2 ATP-binding cassette) includingAla565Thr Arg651Cys and Ala665Thr were not associatedwith T1DM significantly [27]
Association of alleles A2ndashA9 of CD4 with T1DM wasassessed in 200 subjects It was revealed that A3 allele hadnegative (119875 = 0025) and A5 had positive (119875 = 0001)significant association with T1DM [33]
Association of some other genes including osteopontin(rs1126772 polymorphism) integrin 1205724 (rs1449263 polymor-phism) CD44 (rs8193 polymorphism) and TGF120573 (trans-forming growth factor) (+915CG polymorphism) was alsoinvestigated in 2 studies and no significant relation wasobserved between these variants and T1DM [23 29]
322 MODY In this category only one study was found [34]and the association of Val255Met polymorphism of HNF120572and diabetes was investigated in 101 subjects includingMODY subjects their relatives and healthy controls [34]Thestudy was designed as a case control association study andPCR-RFLP and direct sequencing was used for genotyping
of variants Val255Met mutation in this investigation wasobserved in MODY subjects and their relatives but not incontrol group
323 T2DM Related Genes In this subgroup 42 studieswere assessed and all of them were designed as case controlassociation studies [22 35ndash68 70ndash75] except for one whichwas cross sectionally designed [69] In 33 studies PCR- RFLPwas used for genotyping [22 36ndash38 40ndash54 56 58ndash61 63ndash66 69 72ndash75] In 5 of them PCR was used [35 57 62 70 71]and the remaining studies PCR-SCA [39] real-timePCR [55]ARMS-PCR [66] Gap PCR [67] and CSGE (conformation-sensitive gel electrophoresis) sequencing [68] as the genotyp-ing method were applied
Association between two polymorphisms of TCF7L2including rs7903146 (CT) and rs12255372 (GT)was assessedin three studies [38 48 53] In one study investigatingrs7903146 (CT) in 466 subjects significant difference in thefrequency of CC and CT genotypes was observed betweenT2DM and control group (119875 = 0045) [38] However inanother study this polymorphism showed a positive signifi-cant associationwith TT genotype in T2DM (119875 = 0008) [53]Investigation of rs12255372 (GT) polymorphism of TCF7L2in another study showed that among 491 subjects there wasa positive significant association between TT carriers andT2DM (119875 = 0014) [48]
Investigating the association of calreticulinwith T2DM in650 subjects showed two mutations only in case group 9 bpdeletion of 397ndash399 codons and GgtT mutation at IVSII-142[39]
Association of estrogen receptor 120572 and its PvuII(PPPppp) and XbaI(XXXxxx) polymorphism with T2DM intwo studies was assessed [40 49] In one study the significantassociation of PvuII and XbaI polymorphisms with T2DMwas observed (119875 = 0014 and 119875 = 0002 resp) [40] Inanother study it was revealed that pooled Pp+pp and XX+xxmale carriers have positive significant associationwithT2DM(119875 = 0001 and 119875 = 0026 resp) [49]
Association of Pro12Ala polymorphism of PPAR120574 withT2DMwas investigated in three studies [41 69 75] Negativesignificant association of AlaAla genotype with T2DM wasobserved in two studies (119875 = 0003) [41 75] AlaPro carrierswere shown to be positively associated in one study [41] andnegatively associated in another study [75] with T2DM (119875 lt0001 and 119875 = 0003 resp) However in the third studyno significant association was observed between Pro12Alapolymorphism of PPAR120574 and T2DM [69]
Association of different polymorphisms of ApoAI withT2DM was investigated in two studies [43 72] In one studyinvestigation of MSPI polymorphism showed no significantassociation with T2DM [43] In another study it was shownthat G-75A polymorphism of ApoAI was not associated withT2DM while a significant association was found betweenC+83T polymorphism and T2DM (119875 = 0028) [72]
Two studies assessed the association of minus156GgtC poly-morphism of CXCL5 with T2DM [44 65] In one studypositive significant association of GC carriers (119875 = 0006)and negative association of GG carriers (119875 = 001) was foundbetween diabetic patients and healthy controls [44] and
14 Journal of Diabetes Research
in another study positive significant association was foundbetween GC or CC carriers and T2DM (119875 = 0009) [64]
Adiponectin and its association with T2DM were inves-tigated in two studies [56 73] In one study two variantsincluding +45TG and minus11391GA were investigated but nosignificant relation was found between these two polymor-phisms and T2DM [56] However in another study investi-gating +45TG polymorphism of adiponectin it was revealedthat nonobese T2DM subjects had significantly higher TTgenotype (119875 = 004) [73]
In one study that investigated insulin receptor gene thefollowing mutations were found only in T2DM 511CgtA514TgtG 586 and 628TgtA on exon 2 694GgtC 680GgtA onexon 3 1627AgtT on exon 8 ATgtTG on intron 9 2007CgtCTon exon 9 2595CgtCT and 2669GgtCG on exon 13 2706 and2717CgtG 2752CgtT and 2753CgtG on exon 14 and 3471TgtAand 3516TgtG on exon 19 These mutations were not seen incontrol subjects [68]
Other variants which had significant association withT2DM included haptoglobin (allele 2-2) leptin (G-2548Apolymorphism) paraoxonase 2 (Ser311Cys polymorphism)GST (glutathione-S-transferase) M1 and GSTM1GSTT1interaction calpain-10 (SNP (single nucleotide polymor-phism) 43) IRS-1 (G972R polymorphism) and IRS-2(G1057D polymorphism) VDR (vitamin D receptor) (TaqIpolymorphism) KCNJ11 (E23K polymorphism) eNOS(endothelial nitric oxide synthase) VNTR (intron 4 ab pol-ymorphism) resistin (minus420CG polymorphism) and ACE(InsertionDeletion) [35ndash37 45 47 50 55 57 58 64 70]
In contrast to above variants CTLA4 (+49AG poly-morphism) HNF-1120572 (Ala98Val polymorphism) GLP-1R(glucagon-like peptid 1 receptor) (Thr149Met polymor-ohism) SLC30A8 (Arg325Trp polymorphism) GSTP1(Ile105Val polymorphism) glucokinase (minus30GA polymor-phism) SDF-1120573 (stromal derived factor -1 120573) (G801A poly-morphism) ApoE (apolipoprotein E) ENPP1 (ectoenzymenucleotide pyrophosphate phosphodiesterase 1) (K121Q poly-morphism) SUMO4 (small ubiquitin-like modifier 4)Met55Val polymorphism) MTHFR (C677T polymorphism)UCP2 (uncoupling protein 2) (minus866GA polymorphism)5HTTLPR IL-4 (minus590CT polymorphism) IFN-120574 (inter-feron 120574) (+874TA polymorphism) CCR5 (C-C chemokinereceptor type 5) (12057532mutation) HFE (hemochromatosisgene) (H63D C282Y PTPN1 (protein tyrosin Phosphatase1B)minus51delA minus451AgtG minus467TgtC minus1023CgtA minus1045GgtAminus1286 3 bp del ACA minus1291 9 bp del CTAGACTAA poly-morphisms) were not significantly associated with T2DM[22 42 46 50ndash52 54 59ndash63 66 67 71 74]
324 Genes Related to Insulin Resistance In this subgroupfour studies were assessed and all were designed as case-control association studies Three studies used PCR-RFL [7678 79] and one study used real-time PCR [77] for genotyping
The studies assessed in this subgroup showed a positiveassociation of TG carriers of +45TG polymorphism ofadiponectin (119875 = 0032) and Ala allele carriers of Pro12Alapolymorphism of PPAR120574 (119875 = 0036) with T2DM [76 77]A positive significant association of ff carriers of VDR wasalso shown (FokI polymorphism) (119875 = 002) and negative
association of 148insG carriers of PTPN1 (148insG polymor-phism) (119875 = 0041) with insulin resistance index [7879] However no significant association was shown betweenadiponectin receptor-2+795GA and T2DM [76]
325 Genes Related to Cardiovascular Disease in DiabetesDesign of all 11 studies in this subgroup was case-controlassociation study [80ndash84 86ndash90] except one study which wasdesigned as cross sectional [85] PCR-RFLP was used in all ofthem for genotyping [80ndash88 90] except in one study whichused ARMS-PCR method [89]
Paraoxonase 1 (163TA polymorphism) was the only vari-ant in this subgroup which was not significantly associatedwith atherosclerosis risk in T2DM [80] Investigation ofanother polymorphism of Paraoxonase 1 (Q192R) revealedthat diabetics with CAD had significant increase in RRgenotype (119875 lt 005) [81]
Investigating B1 and B2 alleles of CETP TaqI B allele in400 subjects showed that pooling of B1B1+B1B2 and B1B1genotypes had significant association with T2DM and CAD(119875 lt 001) On the other hand assessing the G894T poly-morphism of eNOS showed positive significant associationbetween TG and TT carriers and CAD (119875 lt 005) It was alsoshown that concomitant presence of NOS3 T allele and CEPTB1 allele was significantly associated with T2DM (119875 = 0004)and CAD (119875 = 0002) [83]
Investigation of apolipoprotein E (E2 E3 and E4) allelesshowed the association of E2 and E4 alleles with CAD(119875 lt 0001) [84 87] Also it was shown that interactionof butyrylcholinesterase (BChE K) and apolipoprotein E(ApoE) was associated significantly with CAD and diabetesApoE4BChE K had significant association with lipid profilesas well (119875 lt 005) [87]
Adiponectin +276GT and +45TG were significantlyassociated with CAD (119875 = 0023 and 0033 resp) [82] whileinvestigating minus1612 5A6A polymorphism of MMP-3 (matrixmetalloproteinase 3) showed a significant association withCAS (coronary artery stenosis) (119875 = 0008) [86]
In addition A1166C polymorphism of AT1R (angiotensinI receptor) and minus420CG polymorphism of resistin in dia-betic patients with CAD revealed significant association withdiabetes 119875 = 001 and 119875 = 0009 respectively [84 85]
Another study showed insertion(I)deletion(D) polymor-phismof angiotensin converting enzyme (ACE)DDgenotypewas significantly associated with higher blood pressure (119875 =0026) [89]
Factor V Leiden (G1691A polymorphism) prothrombin(G20210A polymorphism) and MTHFR (methylenetetrahy-drofolate reductase) (C677T polymorphism) were the vari-ants which were not significantly associated with CAD andT2DM in this subgroup [88]
326 Genes Related to Diabetic Nephropathy All of 15 studiesin this subgroup were designed as case-control associationstudies [91ndash106] In 7 studies PCR-RFLP was used forgenotyping [92ndash95 99 102 103] in four studies PCRwas used[98 101 104 105] and in 4 of them both PCR and PCR-RFLPwere used [91 96 97 100]
Journal of Diabetes Research 15
Studying the association of 163AG polymorphism ofSUMO4 showed a positive significant association betweenAA carriers and diabetic nephropathy (119875 lt 005) [93]
Studying the interaction of eNOS4ab and G894Trevealed positive significant association between 4a or 894Tallele carriers and macro- and microalbuminuria (119875 = 001119875 = 002 resp) [91] It was observed that the interaction ofeNOS (G894T polymorphism) andACE (ID alleles) was sig-nificantly associated with more frequent macroalbuminuria(119875 = 0035) [97]
It has also been shown that interaction of eNOS (G894Tpolymorphisms) and MTHFR (C677T and A1298C poly-morphisms) eNOS T1298 C and eNOS T677 T carriershad positive significant association with macroalbuminuriaIn addition significant association of eNOS GT+TT carrierswith lipid profile (119875 lt 005) was shown in this study [99]
C677T andA1298C polymorphisms ofMTHFRwere alsoinvestigated in another study revealing that 677T 1298Cand 677T1298C carriers were significantly associated withmacroalbuminuria (119875 lt 0001) Positive significant asso-ciation when pooling CT+TT genotypes and 677T1298Cwas also found with microalbuminuria (119875 lt 0001) [103]Investigating the interaction of MTHFR (A1298C C677Tpolymorphisms) and ACE (ID alleles) showed a positivesignificant association of ACE D677T (119875 = 0035) and ACED1298C (119875 = 0012) genotypeswithmacroalbuminuria [96]
ACE (ID alleles) polymorphisms were investigated inthree studies In one study positive significant association(119875 lt 001) between DD carriers and progression but notdevelopment of albuminuria was observed [104] In anotherstudy in nephropathic subjects association of DD carriersand T2DM (119875 = 0006) but not nephropathy was revealed[105] However another study did not show significant asso-ciation of ACE with macroalbuminuria [98] Interaction ofACE (ID alleles) with Factor V Leiden (G1691A polymor-phism) was not significant [100]
Association of interleukins including IL-4 and IL-10 withdiabetic nephropathy was also investigated in two studiesStudy of minus592CA polymorphism of IL-10 revealed positivesignificant association between CC carriers and nephropathy(119875 = 0001) [94] and study ofminus590CTpolymorphismof IL-4revealed positive significant association between CT carriersand nephropathy (119875 lt 0001) [101]
Other significant associations between variants and dia-betic nephropathy included AT2R (angiotensin II recep-tor) (minus1332GA polymorphism) VEGF (vascular epitheliumgrowth factor) (+405GC polymorphism) and VDR (TaqIpolymorphism) [92 95 102] ApaI polymorphism of VDRwas not significantly associated with diabetic nephropathy[102]
327 Genes Related to Diabetic Retinopathy All of the 3studies in this subgroup were conducted as case-controlassociation studies [106ndash108]
Investigating nullpositive genotype of GSTM1 in a studywhich used ARMS-PCR for genotyping revealed that nullgenotype is significantly associated with diabetic retinopathy(119875 lt 005) [106] This result was confirmed in another study
by using multiplex PCR as genotyping [107] although nosignificant association between GSTT1 and retinopathy wasfound in this study [107]
Investigating +405GC polymorphism of VEGF alsorevealed positive significant association between GG carriersand diabetic retinopathy (119875 = 0005) [108]
328 Genes Related to Diabetic Foot Ulcer In this subgrouponly one study was found [109] which was case-controldesigned and used ARMS-PCR for genotyping In this studyassociation of minus7CT and minus2578CA polymorphisms ofVEGF with diabetic foot ulcer (DFU) was investigated and apositive significant association betweenAA carriers andDFU(119875 = 003) was observed But no significant association wasfound between minus7CT of VEGF and DFU [109]
4 Discussion
Diabetes mellitus is the eighth most frequent disease leadingcause of death throughout the world and now ranks the fifthfollowing communicable diseases cardiovascular diseasecancer and injuries [110] Prevalence of diabetes mellitus isincreasing worldwide [6]
Type 2 diabetes is the most frequent type of diabetesmellitus [110 111] Multiple genes and environmental factorsaffect the prevalence of T2DM Systematic review and meta-analysis studies have assessed the association between dif-ferent genes and T2DM Glutathione-S-transferase includingGSTMI GSTM1 and GSTP1 are important genes and theirassociation with diabetes has been investigated in two meta-analysis studies [112 113] It was revealed that null genotypeof both GSTM1 and GSTT1 could be as a risk factor fordiabetes while no significant association was found betweenGSTP1 and diabetes [112 113] These results are in linewith our finding and confirming the association of the nullgenotype of GSTT1 and GSTM1 with T2DM in Iranianpopulation [50] The relation between GSTT1 and GSTM1and diabetic retinopathy has also been shown in Iranianpopulation [106 107]
MTHFR is another important gene in association withT2DM and other related complications No associationof C677T polymorphism of MTHFR gene was found inAfricans Asians and Caucasians [114] MTHFR is a genewhich is involved in DNA methylation and synthesis andregulated folate activity It has been reported that mutanthomozygote and heterozygote of C677T polymorphism ofMTHFR increase plasma homocysteine which is an impor-tant factor leading to diabetic nephropathy (DN) and as aresult C677T polymorphism of MTHFR can be associatedwith the development of DN In Caucasians this associationhas also been observed [115] In Iranian population in linewith other populations no significant association was foundbetween MTHFR polymorphisms and T2DM [63] althoughsignificant association of 677T and 1298C alleles with diabeticnephropathy was observed [87] Interaction of two polymor-phisms and also interaction of MTHFR polymorphisms withother genes such as ACE and eNOS showed an associationwith development of DN [96 99]
16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
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Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
12 Journal of Diabetes Research
Table1Con
tinued
Reference
GenesSNPor
allele
Patie
ntsrsquocharacteris
tics
City
Stud
ydesig
nMetho
dSign
ificant
association
Nikzamiretal2009
[104]
ACEID
129T
2DMm
icrolbum
iunira
48T2
DMm
acroalbu
minuria
and145T
2DMnormoalbum
inuria
594plusmn85y
rMF
Tehran
Crosssectio
nal
PCR
Positives
ignificantassociatio
nbetweenDDcarriersand
progressionof
albu
minuria
(119875lt001)b
utno
tits
developm
ent
Nikzamiretal2006
[105]
ACEID
85T2
DMD
N85T2
DMnon
-DN
and91
healthy37ndash6
7yrMF
Tehran
Case
control
PCR
Positives
ignificantassociatio
nbetweenDDcarriersandT2
DM
(119875=0006)b
utno
tDN
T2DM
patie
ntsa
ndretin
opathy
Abbasietal2013
[106]
GST
M1n
ullp
ositive
80DRand80
healthy
30ndash70y
rMF
Rasht
Case
control
ARM
S-PC
RNullgenotypes
ignificant
association
Plt005
Dadbinp
oure
tal2013
[107]
(i)GST
M1n
ullp
ositive
(ii)G
STT1nullp
ositive
57DRand58
non-DR
35ndash6
5yrMF
Yazd
Case
control
Multip
lexPC
R
(i)Nullgenotypeo
fGST
M1o
rGST
T1sig
nificantassociatio
n(119875=004)
(ii)N
onsig
nificantassociatio
nof
GST
T1nu
llcarrierswith
DR
Fegh
hietal2011[108]
VEG
F+4
05G
C119
diabeticsw
ithPD
Rand279
diabeticsw
ithNPD
R47ndash6
6yrMF
Ahvaz
Case
control
PCR-RF
LPPo
sitives
ignificantassociatio
nbetweenGGcarriersanddiabetic
retin
opathy
(P=0005)
T2DM
patie
ntsa
ndfoot
ulcer
Amolietal2011[109]
(i)VEG
Fminus7C
T(ii)V
EGFminus2578CA
247T2
DM
with
DFU
241
T2DM
with
outD
FUand
98healthy
43ndash6
4MF
Tehran
Case
control
ARM
S-PC
R
(i)Non
significantassociatio
nof
minus7C
Tcarrierswith
DFU
(ii)P
ositive
significant
associationbetweenAAcarriers
andDFU
(P=003)
SNPsin
glenu
cleotid
epo
lymorph
ismT
1DMtype1d
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4T2
DMtype2diabetes
mellitusP
CRp
olym
erasechainreactio
nRF
LPrestrictio
nfragmentlengthpo
lymorph
ismILinterle
ukinSS-PC
Rsequ
ence
specificP
CRV
DR
vitamin
DreceptorT
AP2
transpo
rter
2AT
P-bind
ingcassetteA
RMS-PC
Ram
plificatio
nrefractory
mutationsyste
mPC
RPC
R-SSPPC
Rsin
glespecificprim
erT
GF120573
transform
inggrow
thfactor120573D
Md
iabetesm
ellitusC
TLA-
4cytotoxicTlymph
ocyteassociated
antig
en4
MODY
maturity
onsetd
iabeteso
fthe
youn
gHNF-
1120572h
epatocytenu
clear
factor
1120572M
VCm
icrovascular
complicationsT
CF7L
2transcrip
tionfactor
7-lik
e2PC
R-SSCA
PCR
singlestr
andconformationpo
lymorph
ismanalysis
ER120572estr
ogen
receptor120572N
D
nond
iabeticsTC
totalcholesterolTG
trig
lycerid
esP
PAR-1205742peroxisomep
roliferator-activates
receptor120574G
LP-1R
glucagon
-like
peptid
1receptorAPO
apo
lipop
roteinC
XCL5chemokineC
-X-C
motifligand
5SD
F-1120573stro
malderiv
edfactor-1120573IRS
1amp2insulin
receptor
substrate1amp
2GSTglutathione-S-tr
ansfe
raseSLC
30A8solublecarrier3
0A8KC
NJPo
tassium
inwardly-rectify
ingchanneleN
OSendo
thelial
nitricoxidesynthaseVNTR
variablen
umbero
ftandem
repeatsEN
PP1ectoenzymen
ucleotidep
yrop
hosphateph
osph
odieste
rase1SU
MOsmallubiqu
itin-lik
emod
ifier4UCP
2un
coup
lingp
rotein
2MTH
FR
methylenetetrahydrofolateredu
ctaseIFN120574interferon120574C
CR5C-
Cchem
okiner
eceptortype5
INSR
insulin
receptorC
SGE
conformation-sensitive
gelelectroph
oresis
ACE
angiotensin
Icon
vertingenzyme
HFE
hem
ochrom
atosisgenePTP
N1proteintyrosin
Phosph
atase1B
CADcoron
arya
rteryd
iseaseCE
TPcho
leste
ryleste
rtransferp
roteinA
T1R
angiotensin
IreceptorMMP3
matrix
metalloproteinase
3CA
Scoronary
artery
steno
sisB
ChEK
Butyrylcho
linesteraseK
DNdiabetic
neph
ropathyAT
2Rang
iotensin
IIreceptorV
EGFvascularepith
elium
grow
thfactorD
Rdiabeticretin
opathy
PDR
proliferativ
ediabetic
retin
opathy
NPD
Rno
n-PD
RDFU
diabetic
foot
ulcer
Journal of Diabetes Research 13
321 T1DM Related Genes All the studies in this subgroupincluding 12 studies [22ndash33] were in a case control studydesign using PCR (polymerase chain reaction) [33] PCR-RFLP (restriction fragment length polymorphism) [22 2325 26 32] PCR-SSP (single specific primer) [24 28ndash32]and ARMS-PCR (amplification refractory mutation systemPCR) [27] method In all studies both men and women wereincluded and the overall 2519 subjects were under 40 yearsold
Association of interleukins including IL-18 (interleukin)and IL-12 with T1DM revealed that the minus137CG polymor-phism of IL-18 had significant association with T1DM (119875 =0037 119875 = 00001) while no significant relation was observedbetween minus607AC variant of this gene and T1DM [24 28]Investigating IL-12 also showed that there was a significantassociation between +1188AC polymorphism of this geneand T1DM (119875 = 0035) [30]
In 2 studies the association of +49AG variant of CTLA-4 (cytotoxic T lymphocyte associated antigen 4) was investi-gated and it was revealed that there was a positive significantassociation between AG genotype and T1DM (119875 = 001 119875 lt0001) [22 32] One of these studies also revealed that therewas a negative relation betweenAA genotype and T1DM [32]
Vitamin D receptor (VDR) was investigated in 2 studies[25 26] Both of them assessed the association of FokI BsmIApaI and TaqI variants of VDR with T1DM In one studywhichwas performed on 114 subjects Aa (119875 = 0003) FF (119875 =0008) and Bb (119875 = 0014) genotypes were shown to be pos-itively associated with T1DM but no significant associationwas observed between TaqI polymorphism and T1DM [25]Another study which was performed on 187 subjects showedno significant association between T1DM and FokI BsmIand ApaI However TT genotype was observed to be morefrequent in controls (119875 = 0007) and negatively associatedwith T1DM [26]
Different polymorphisms of TAP2 and their associationwith T1DM were investigated in 191 subjects It was shownthat Ile379Val and Stop687Gln had significant associationwith T1DM (119875 = 0001 and 119875 = 0013 resp) Other variantsof TAP2 (transporter 2 ATP-binding cassette) includingAla565Thr Arg651Cys and Ala665Thr were not associatedwith T1DM significantly [27]
Association of alleles A2ndashA9 of CD4 with T1DM wasassessed in 200 subjects It was revealed that A3 allele hadnegative (119875 = 0025) and A5 had positive (119875 = 0001)significant association with T1DM [33]
Association of some other genes including osteopontin(rs1126772 polymorphism) integrin 1205724 (rs1449263 polymor-phism) CD44 (rs8193 polymorphism) and TGF120573 (trans-forming growth factor) (+915CG polymorphism) was alsoinvestigated in 2 studies and no significant relation wasobserved between these variants and T1DM [23 29]
322 MODY In this category only one study was found [34]and the association of Val255Met polymorphism of HNF120572and diabetes was investigated in 101 subjects includingMODY subjects their relatives and healthy controls [34]Thestudy was designed as a case control association study andPCR-RFLP and direct sequencing was used for genotyping
of variants Val255Met mutation in this investigation wasobserved in MODY subjects and their relatives but not incontrol group
323 T2DM Related Genes In this subgroup 42 studieswere assessed and all of them were designed as case controlassociation studies [22 35ndash68 70ndash75] except for one whichwas cross sectionally designed [69] In 33 studies PCR- RFLPwas used for genotyping [22 36ndash38 40ndash54 56 58ndash61 63ndash66 69 72ndash75] In 5 of them PCR was used [35 57 62 70 71]and the remaining studies PCR-SCA [39] real-timePCR [55]ARMS-PCR [66] Gap PCR [67] and CSGE (conformation-sensitive gel electrophoresis) sequencing [68] as the genotyp-ing method were applied
Association between two polymorphisms of TCF7L2including rs7903146 (CT) and rs12255372 (GT)was assessedin three studies [38 48 53] In one study investigatingrs7903146 (CT) in 466 subjects significant difference in thefrequency of CC and CT genotypes was observed betweenT2DM and control group (119875 = 0045) [38] However inanother study this polymorphism showed a positive signifi-cant associationwith TT genotype in T2DM (119875 = 0008) [53]Investigation of rs12255372 (GT) polymorphism of TCF7L2in another study showed that among 491 subjects there wasa positive significant association between TT carriers andT2DM (119875 = 0014) [48]
Investigating the association of calreticulinwith T2DM in650 subjects showed two mutations only in case group 9 bpdeletion of 397ndash399 codons and GgtT mutation at IVSII-142[39]
Association of estrogen receptor 120572 and its PvuII(PPPppp) and XbaI(XXXxxx) polymorphism with T2DM intwo studies was assessed [40 49] In one study the significantassociation of PvuII and XbaI polymorphisms with T2DMwas observed (119875 = 0014 and 119875 = 0002 resp) [40] Inanother study it was revealed that pooled Pp+pp and XX+xxmale carriers have positive significant associationwithT2DM(119875 = 0001 and 119875 = 0026 resp) [49]
Association of Pro12Ala polymorphism of PPAR120574 withT2DMwas investigated in three studies [41 69 75] Negativesignificant association of AlaAla genotype with T2DM wasobserved in two studies (119875 = 0003) [41 75] AlaPro carrierswere shown to be positively associated in one study [41] andnegatively associated in another study [75] with T2DM (119875 lt0001 and 119875 = 0003 resp) However in the third studyno significant association was observed between Pro12Alapolymorphism of PPAR120574 and T2DM [69]
Association of different polymorphisms of ApoAI withT2DM was investigated in two studies [43 72] In one studyinvestigation of MSPI polymorphism showed no significantassociation with T2DM [43] In another study it was shownthat G-75A polymorphism of ApoAI was not associated withT2DM while a significant association was found betweenC+83T polymorphism and T2DM (119875 = 0028) [72]
Two studies assessed the association of minus156GgtC poly-morphism of CXCL5 with T2DM [44 65] In one studypositive significant association of GC carriers (119875 = 0006)and negative association of GG carriers (119875 = 001) was foundbetween diabetic patients and healthy controls [44] and
14 Journal of Diabetes Research
in another study positive significant association was foundbetween GC or CC carriers and T2DM (119875 = 0009) [64]
Adiponectin and its association with T2DM were inves-tigated in two studies [56 73] In one study two variantsincluding +45TG and minus11391GA were investigated but nosignificant relation was found between these two polymor-phisms and T2DM [56] However in another study investi-gating +45TG polymorphism of adiponectin it was revealedthat nonobese T2DM subjects had significantly higher TTgenotype (119875 = 004) [73]
In one study that investigated insulin receptor gene thefollowing mutations were found only in T2DM 511CgtA514TgtG 586 and 628TgtA on exon 2 694GgtC 680GgtA onexon 3 1627AgtT on exon 8 ATgtTG on intron 9 2007CgtCTon exon 9 2595CgtCT and 2669GgtCG on exon 13 2706 and2717CgtG 2752CgtT and 2753CgtG on exon 14 and 3471TgtAand 3516TgtG on exon 19 These mutations were not seen incontrol subjects [68]
Other variants which had significant association withT2DM included haptoglobin (allele 2-2) leptin (G-2548Apolymorphism) paraoxonase 2 (Ser311Cys polymorphism)GST (glutathione-S-transferase) M1 and GSTM1GSTT1interaction calpain-10 (SNP (single nucleotide polymor-phism) 43) IRS-1 (G972R polymorphism) and IRS-2(G1057D polymorphism) VDR (vitamin D receptor) (TaqIpolymorphism) KCNJ11 (E23K polymorphism) eNOS(endothelial nitric oxide synthase) VNTR (intron 4 ab pol-ymorphism) resistin (minus420CG polymorphism) and ACE(InsertionDeletion) [35ndash37 45 47 50 55 57 58 64 70]
In contrast to above variants CTLA4 (+49AG poly-morphism) HNF-1120572 (Ala98Val polymorphism) GLP-1R(glucagon-like peptid 1 receptor) (Thr149Met polymor-ohism) SLC30A8 (Arg325Trp polymorphism) GSTP1(Ile105Val polymorphism) glucokinase (minus30GA polymor-phism) SDF-1120573 (stromal derived factor -1 120573) (G801A poly-morphism) ApoE (apolipoprotein E) ENPP1 (ectoenzymenucleotide pyrophosphate phosphodiesterase 1) (K121Q poly-morphism) SUMO4 (small ubiquitin-like modifier 4)Met55Val polymorphism) MTHFR (C677T polymorphism)UCP2 (uncoupling protein 2) (minus866GA polymorphism)5HTTLPR IL-4 (minus590CT polymorphism) IFN-120574 (inter-feron 120574) (+874TA polymorphism) CCR5 (C-C chemokinereceptor type 5) (12057532mutation) HFE (hemochromatosisgene) (H63D C282Y PTPN1 (protein tyrosin Phosphatase1B)minus51delA minus451AgtG minus467TgtC minus1023CgtA minus1045GgtAminus1286 3 bp del ACA minus1291 9 bp del CTAGACTAA poly-morphisms) were not significantly associated with T2DM[22 42 46 50ndash52 54 59ndash63 66 67 71 74]
324 Genes Related to Insulin Resistance In this subgroupfour studies were assessed and all were designed as case-control association studies Three studies used PCR-RFL [7678 79] and one study used real-time PCR [77] for genotyping
The studies assessed in this subgroup showed a positiveassociation of TG carriers of +45TG polymorphism ofadiponectin (119875 = 0032) and Ala allele carriers of Pro12Alapolymorphism of PPAR120574 (119875 = 0036) with T2DM [76 77]A positive significant association of ff carriers of VDR wasalso shown (FokI polymorphism) (119875 = 002) and negative
association of 148insG carriers of PTPN1 (148insG polymor-phism) (119875 = 0041) with insulin resistance index [7879] However no significant association was shown betweenadiponectin receptor-2+795GA and T2DM [76]
325 Genes Related to Cardiovascular Disease in DiabetesDesign of all 11 studies in this subgroup was case-controlassociation study [80ndash84 86ndash90] except one study which wasdesigned as cross sectional [85] PCR-RFLP was used in all ofthem for genotyping [80ndash88 90] except in one study whichused ARMS-PCR method [89]
Paraoxonase 1 (163TA polymorphism) was the only vari-ant in this subgroup which was not significantly associatedwith atherosclerosis risk in T2DM [80] Investigation ofanother polymorphism of Paraoxonase 1 (Q192R) revealedthat diabetics with CAD had significant increase in RRgenotype (119875 lt 005) [81]
Investigating B1 and B2 alleles of CETP TaqI B allele in400 subjects showed that pooling of B1B1+B1B2 and B1B1genotypes had significant association with T2DM and CAD(119875 lt 001) On the other hand assessing the G894T poly-morphism of eNOS showed positive significant associationbetween TG and TT carriers and CAD (119875 lt 005) It was alsoshown that concomitant presence of NOS3 T allele and CEPTB1 allele was significantly associated with T2DM (119875 = 0004)and CAD (119875 = 0002) [83]
Investigation of apolipoprotein E (E2 E3 and E4) allelesshowed the association of E2 and E4 alleles with CAD(119875 lt 0001) [84 87] Also it was shown that interactionof butyrylcholinesterase (BChE K) and apolipoprotein E(ApoE) was associated significantly with CAD and diabetesApoE4BChE K had significant association with lipid profilesas well (119875 lt 005) [87]
Adiponectin +276GT and +45TG were significantlyassociated with CAD (119875 = 0023 and 0033 resp) [82] whileinvestigating minus1612 5A6A polymorphism of MMP-3 (matrixmetalloproteinase 3) showed a significant association withCAS (coronary artery stenosis) (119875 = 0008) [86]
In addition A1166C polymorphism of AT1R (angiotensinI receptor) and minus420CG polymorphism of resistin in dia-betic patients with CAD revealed significant association withdiabetes 119875 = 001 and 119875 = 0009 respectively [84 85]
Another study showed insertion(I)deletion(D) polymor-phismof angiotensin converting enzyme (ACE)DDgenotypewas significantly associated with higher blood pressure (119875 =0026) [89]
Factor V Leiden (G1691A polymorphism) prothrombin(G20210A polymorphism) and MTHFR (methylenetetrahy-drofolate reductase) (C677T polymorphism) were the vari-ants which were not significantly associated with CAD andT2DM in this subgroup [88]
326 Genes Related to Diabetic Nephropathy All of 15 studiesin this subgroup were designed as case-control associationstudies [91ndash106] In 7 studies PCR-RFLP was used forgenotyping [92ndash95 99 102 103] in four studies PCRwas used[98 101 104 105] and in 4 of them both PCR and PCR-RFLPwere used [91 96 97 100]
Journal of Diabetes Research 15
Studying the association of 163AG polymorphism ofSUMO4 showed a positive significant association betweenAA carriers and diabetic nephropathy (119875 lt 005) [93]
Studying the interaction of eNOS4ab and G894Trevealed positive significant association between 4a or 894Tallele carriers and macro- and microalbuminuria (119875 = 001119875 = 002 resp) [91] It was observed that the interaction ofeNOS (G894T polymorphism) andACE (ID alleles) was sig-nificantly associated with more frequent macroalbuminuria(119875 = 0035) [97]
It has also been shown that interaction of eNOS (G894Tpolymorphisms) and MTHFR (C677T and A1298C poly-morphisms) eNOS T1298 C and eNOS T677 T carriershad positive significant association with macroalbuminuriaIn addition significant association of eNOS GT+TT carrierswith lipid profile (119875 lt 005) was shown in this study [99]
C677T andA1298C polymorphisms ofMTHFRwere alsoinvestigated in another study revealing that 677T 1298Cand 677T1298C carriers were significantly associated withmacroalbuminuria (119875 lt 0001) Positive significant asso-ciation when pooling CT+TT genotypes and 677T1298Cwas also found with microalbuminuria (119875 lt 0001) [103]Investigating the interaction of MTHFR (A1298C C677Tpolymorphisms) and ACE (ID alleles) showed a positivesignificant association of ACE D677T (119875 = 0035) and ACED1298C (119875 = 0012) genotypeswithmacroalbuminuria [96]
ACE (ID alleles) polymorphisms were investigated inthree studies In one study positive significant association(119875 lt 001) between DD carriers and progression but notdevelopment of albuminuria was observed [104] In anotherstudy in nephropathic subjects association of DD carriersand T2DM (119875 = 0006) but not nephropathy was revealed[105] However another study did not show significant asso-ciation of ACE with macroalbuminuria [98] Interaction ofACE (ID alleles) with Factor V Leiden (G1691A polymor-phism) was not significant [100]
Association of interleukins including IL-4 and IL-10 withdiabetic nephropathy was also investigated in two studiesStudy of minus592CA polymorphism of IL-10 revealed positivesignificant association between CC carriers and nephropathy(119875 = 0001) [94] and study ofminus590CTpolymorphismof IL-4revealed positive significant association between CT carriersand nephropathy (119875 lt 0001) [101]
Other significant associations between variants and dia-betic nephropathy included AT2R (angiotensin II recep-tor) (minus1332GA polymorphism) VEGF (vascular epitheliumgrowth factor) (+405GC polymorphism) and VDR (TaqIpolymorphism) [92 95 102] ApaI polymorphism of VDRwas not significantly associated with diabetic nephropathy[102]
327 Genes Related to Diabetic Retinopathy All of the 3studies in this subgroup were conducted as case-controlassociation studies [106ndash108]
Investigating nullpositive genotype of GSTM1 in a studywhich used ARMS-PCR for genotyping revealed that nullgenotype is significantly associated with diabetic retinopathy(119875 lt 005) [106] This result was confirmed in another study
by using multiplex PCR as genotyping [107] although nosignificant association between GSTT1 and retinopathy wasfound in this study [107]
Investigating +405GC polymorphism of VEGF alsorevealed positive significant association between GG carriersand diabetic retinopathy (119875 = 0005) [108]
328 Genes Related to Diabetic Foot Ulcer In this subgrouponly one study was found [109] which was case-controldesigned and used ARMS-PCR for genotyping In this studyassociation of minus7CT and minus2578CA polymorphisms ofVEGF with diabetic foot ulcer (DFU) was investigated and apositive significant association betweenAA carriers andDFU(119875 = 003) was observed But no significant association wasfound between minus7CT of VEGF and DFU [109]
4 Discussion
Diabetes mellitus is the eighth most frequent disease leadingcause of death throughout the world and now ranks the fifthfollowing communicable diseases cardiovascular diseasecancer and injuries [110] Prevalence of diabetes mellitus isincreasing worldwide [6]
Type 2 diabetes is the most frequent type of diabetesmellitus [110 111] Multiple genes and environmental factorsaffect the prevalence of T2DM Systematic review and meta-analysis studies have assessed the association between dif-ferent genes and T2DM Glutathione-S-transferase includingGSTMI GSTM1 and GSTP1 are important genes and theirassociation with diabetes has been investigated in two meta-analysis studies [112 113] It was revealed that null genotypeof both GSTM1 and GSTT1 could be as a risk factor fordiabetes while no significant association was found betweenGSTP1 and diabetes [112 113] These results are in linewith our finding and confirming the association of the nullgenotype of GSTT1 and GSTM1 with T2DM in Iranianpopulation [50] The relation between GSTT1 and GSTM1and diabetic retinopathy has also been shown in Iranianpopulation [106 107]
MTHFR is another important gene in association withT2DM and other related complications No associationof C677T polymorphism of MTHFR gene was found inAfricans Asians and Caucasians [114] MTHFR is a genewhich is involved in DNA methylation and synthesis andregulated folate activity It has been reported that mutanthomozygote and heterozygote of C677T polymorphism ofMTHFR increase plasma homocysteine which is an impor-tant factor leading to diabetic nephropathy (DN) and as aresult C677T polymorphism of MTHFR can be associatedwith the development of DN In Caucasians this associationhas also been observed [115] In Iranian population in linewith other populations no significant association was foundbetween MTHFR polymorphisms and T2DM [63] althoughsignificant association of 677T and 1298C alleles with diabeticnephropathy was observed [87] Interaction of two polymor-phisms and also interaction of MTHFR polymorphisms withother genes such as ACE and eNOS showed an associationwith development of DN [96 99]
16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Journal of Diabetes Research 13
321 T1DM Related Genes All the studies in this subgroupincluding 12 studies [22ndash33] were in a case control studydesign using PCR (polymerase chain reaction) [33] PCR-RFLP (restriction fragment length polymorphism) [22 2325 26 32] PCR-SSP (single specific primer) [24 28ndash32]and ARMS-PCR (amplification refractory mutation systemPCR) [27] method In all studies both men and women wereincluded and the overall 2519 subjects were under 40 yearsold
Association of interleukins including IL-18 (interleukin)and IL-12 with T1DM revealed that the minus137CG polymor-phism of IL-18 had significant association with T1DM (119875 =0037 119875 = 00001) while no significant relation was observedbetween minus607AC variant of this gene and T1DM [24 28]Investigating IL-12 also showed that there was a significantassociation between +1188AC polymorphism of this geneand T1DM (119875 = 0035) [30]
In 2 studies the association of +49AG variant of CTLA-4 (cytotoxic T lymphocyte associated antigen 4) was investi-gated and it was revealed that there was a positive significantassociation between AG genotype and T1DM (119875 = 001 119875 lt0001) [22 32] One of these studies also revealed that therewas a negative relation betweenAA genotype and T1DM [32]
Vitamin D receptor (VDR) was investigated in 2 studies[25 26] Both of them assessed the association of FokI BsmIApaI and TaqI variants of VDR with T1DM In one studywhichwas performed on 114 subjects Aa (119875 = 0003) FF (119875 =0008) and Bb (119875 = 0014) genotypes were shown to be pos-itively associated with T1DM but no significant associationwas observed between TaqI polymorphism and T1DM [25]Another study which was performed on 187 subjects showedno significant association between T1DM and FokI BsmIand ApaI However TT genotype was observed to be morefrequent in controls (119875 = 0007) and negatively associatedwith T1DM [26]
Different polymorphisms of TAP2 and their associationwith T1DM were investigated in 191 subjects It was shownthat Ile379Val and Stop687Gln had significant associationwith T1DM (119875 = 0001 and 119875 = 0013 resp) Other variantsof TAP2 (transporter 2 ATP-binding cassette) includingAla565Thr Arg651Cys and Ala665Thr were not associatedwith T1DM significantly [27]
Association of alleles A2ndashA9 of CD4 with T1DM wasassessed in 200 subjects It was revealed that A3 allele hadnegative (119875 = 0025) and A5 had positive (119875 = 0001)significant association with T1DM [33]
Association of some other genes including osteopontin(rs1126772 polymorphism) integrin 1205724 (rs1449263 polymor-phism) CD44 (rs8193 polymorphism) and TGF120573 (trans-forming growth factor) (+915CG polymorphism) was alsoinvestigated in 2 studies and no significant relation wasobserved between these variants and T1DM [23 29]
322 MODY In this category only one study was found [34]and the association of Val255Met polymorphism of HNF120572and diabetes was investigated in 101 subjects includingMODY subjects their relatives and healthy controls [34]Thestudy was designed as a case control association study andPCR-RFLP and direct sequencing was used for genotyping
of variants Val255Met mutation in this investigation wasobserved in MODY subjects and their relatives but not incontrol group
323 T2DM Related Genes In this subgroup 42 studieswere assessed and all of them were designed as case controlassociation studies [22 35ndash68 70ndash75] except for one whichwas cross sectionally designed [69] In 33 studies PCR- RFLPwas used for genotyping [22 36ndash38 40ndash54 56 58ndash61 63ndash66 69 72ndash75] In 5 of them PCR was used [35 57 62 70 71]and the remaining studies PCR-SCA [39] real-timePCR [55]ARMS-PCR [66] Gap PCR [67] and CSGE (conformation-sensitive gel electrophoresis) sequencing [68] as the genotyp-ing method were applied
Association between two polymorphisms of TCF7L2including rs7903146 (CT) and rs12255372 (GT)was assessedin three studies [38 48 53] In one study investigatingrs7903146 (CT) in 466 subjects significant difference in thefrequency of CC and CT genotypes was observed betweenT2DM and control group (119875 = 0045) [38] However inanother study this polymorphism showed a positive signifi-cant associationwith TT genotype in T2DM (119875 = 0008) [53]Investigation of rs12255372 (GT) polymorphism of TCF7L2in another study showed that among 491 subjects there wasa positive significant association between TT carriers andT2DM (119875 = 0014) [48]
Investigating the association of calreticulinwith T2DM in650 subjects showed two mutations only in case group 9 bpdeletion of 397ndash399 codons and GgtT mutation at IVSII-142[39]
Association of estrogen receptor 120572 and its PvuII(PPPppp) and XbaI(XXXxxx) polymorphism with T2DM intwo studies was assessed [40 49] In one study the significantassociation of PvuII and XbaI polymorphisms with T2DMwas observed (119875 = 0014 and 119875 = 0002 resp) [40] Inanother study it was revealed that pooled Pp+pp and XX+xxmale carriers have positive significant associationwithT2DM(119875 = 0001 and 119875 = 0026 resp) [49]
Association of Pro12Ala polymorphism of PPAR120574 withT2DMwas investigated in three studies [41 69 75] Negativesignificant association of AlaAla genotype with T2DM wasobserved in two studies (119875 = 0003) [41 75] AlaPro carrierswere shown to be positively associated in one study [41] andnegatively associated in another study [75] with T2DM (119875 lt0001 and 119875 = 0003 resp) However in the third studyno significant association was observed between Pro12Alapolymorphism of PPAR120574 and T2DM [69]
Association of different polymorphisms of ApoAI withT2DM was investigated in two studies [43 72] In one studyinvestigation of MSPI polymorphism showed no significantassociation with T2DM [43] In another study it was shownthat G-75A polymorphism of ApoAI was not associated withT2DM while a significant association was found betweenC+83T polymorphism and T2DM (119875 = 0028) [72]
Two studies assessed the association of minus156GgtC poly-morphism of CXCL5 with T2DM [44 65] In one studypositive significant association of GC carriers (119875 = 0006)and negative association of GG carriers (119875 = 001) was foundbetween diabetic patients and healthy controls [44] and
14 Journal of Diabetes Research
in another study positive significant association was foundbetween GC or CC carriers and T2DM (119875 = 0009) [64]
Adiponectin and its association with T2DM were inves-tigated in two studies [56 73] In one study two variantsincluding +45TG and minus11391GA were investigated but nosignificant relation was found between these two polymor-phisms and T2DM [56] However in another study investi-gating +45TG polymorphism of adiponectin it was revealedthat nonobese T2DM subjects had significantly higher TTgenotype (119875 = 004) [73]
In one study that investigated insulin receptor gene thefollowing mutations were found only in T2DM 511CgtA514TgtG 586 and 628TgtA on exon 2 694GgtC 680GgtA onexon 3 1627AgtT on exon 8 ATgtTG on intron 9 2007CgtCTon exon 9 2595CgtCT and 2669GgtCG on exon 13 2706 and2717CgtG 2752CgtT and 2753CgtG on exon 14 and 3471TgtAand 3516TgtG on exon 19 These mutations were not seen incontrol subjects [68]
Other variants which had significant association withT2DM included haptoglobin (allele 2-2) leptin (G-2548Apolymorphism) paraoxonase 2 (Ser311Cys polymorphism)GST (glutathione-S-transferase) M1 and GSTM1GSTT1interaction calpain-10 (SNP (single nucleotide polymor-phism) 43) IRS-1 (G972R polymorphism) and IRS-2(G1057D polymorphism) VDR (vitamin D receptor) (TaqIpolymorphism) KCNJ11 (E23K polymorphism) eNOS(endothelial nitric oxide synthase) VNTR (intron 4 ab pol-ymorphism) resistin (minus420CG polymorphism) and ACE(InsertionDeletion) [35ndash37 45 47 50 55 57 58 64 70]
In contrast to above variants CTLA4 (+49AG poly-morphism) HNF-1120572 (Ala98Val polymorphism) GLP-1R(glucagon-like peptid 1 receptor) (Thr149Met polymor-ohism) SLC30A8 (Arg325Trp polymorphism) GSTP1(Ile105Val polymorphism) glucokinase (minus30GA polymor-phism) SDF-1120573 (stromal derived factor -1 120573) (G801A poly-morphism) ApoE (apolipoprotein E) ENPP1 (ectoenzymenucleotide pyrophosphate phosphodiesterase 1) (K121Q poly-morphism) SUMO4 (small ubiquitin-like modifier 4)Met55Val polymorphism) MTHFR (C677T polymorphism)UCP2 (uncoupling protein 2) (minus866GA polymorphism)5HTTLPR IL-4 (minus590CT polymorphism) IFN-120574 (inter-feron 120574) (+874TA polymorphism) CCR5 (C-C chemokinereceptor type 5) (12057532mutation) HFE (hemochromatosisgene) (H63D C282Y PTPN1 (protein tyrosin Phosphatase1B)minus51delA minus451AgtG minus467TgtC minus1023CgtA minus1045GgtAminus1286 3 bp del ACA minus1291 9 bp del CTAGACTAA poly-morphisms) were not significantly associated with T2DM[22 42 46 50ndash52 54 59ndash63 66 67 71 74]
324 Genes Related to Insulin Resistance In this subgroupfour studies were assessed and all were designed as case-control association studies Three studies used PCR-RFL [7678 79] and one study used real-time PCR [77] for genotyping
The studies assessed in this subgroup showed a positiveassociation of TG carriers of +45TG polymorphism ofadiponectin (119875 = 0032) and Ala allele carriers of Pro12Alapolymorphism of PPAR120574 (119875 = 0036) with T2DM [76 77]A positive significant association of ff carriers of VDR wasalso shown (FokI polymorphism) (119875 = 002) and negative
association of 148insG carriers of PTPN1 (148insG polymor-phism) (119875 = 0041) with insulin resistance index [7879] However no significant association was shown betweenadiponectin receptor-2+795GA and T2DM [76]
325 Genes Related to Cardiovascular Disease in DiabetesDesign of all 11 studies in this subgroup was case-controlassociation study [80ndash84 86ndash90] except one study which wasdesigned as cross sectional [85] PCR-RFLP was used in all ofthem for genotyping [80ndash88 90] except in one study whichused ARMS-PCR method [89]
Paraoxonase 1 (163TA polymorphism) was the only vari-ant in this subgroup which was not significantly associatedwith atherosclerosis risk in T2DM [80] Investigation ofanother polymorphism of Paraoxonase 1 (Q192R) revealedthat diabetics with CAD had significant increase in RRgenotype (119875 lt 005) [81]
Investigating B1 and B2 alleles of CETP TaqI B allele in400 subjects showed that pooling of B1B1+B1B2 and B1B1genotypes had significant association with T2DM and CAD(119875 lt 001) On the other hand assessing the G894T poly-morphism of eNOS showed positive significant associationbetween TG and TT carriers and CAD (119875 lt 005) It was alsoshown that concomitant presence of NOS3 T allele and CEPTB1 allele was significantly associated with T2DM (119875 = 0004)and CAD (119875 = 0002) [83]
Investigation of apolipoprotein E (E2 E3 and E4) allelesshowed the association of E2 and E4 alleles with CAD(119875 lt 0001) [84 87] Also it was shown that interactionof butyrylcholinesterase (BChE K) and apolipoprotein E(ApoE) was associated significantly with CAD and diabetesApoE4BChE K had significant association with lipid profilesas well (119875 lt 005) [87]
Adiponectin +276GT and +45TG were significantlyassociated with CAD (119875 = 0023 and 0033 resp) [82] whileinvestigating minus1612 5A6A polymorphism of MMP-3 (matrixmetalloproteinase 3) showed a significant association withCAS (coronary artery stenosis) (119875 = 0008) [86]
In addition A1166C polymorphism of AT1R (angiotensinI receptor) and minus420CG polymorphism of resistin in dia-betic patients with CAD revealed significant association withdiabetes 119875 = 001 and 119875 = 0009 respectively [84 85]
Another study showed insertion(I)deletion(D) polymor-phismof angiotensin converting enzyme (ACE)DDgenotypewas significantly associated with higher blood pressure (119875 =0026) [89]
Factor V Leiden (G1691A polymorphism) prothrombin(G20210A polymorphism) and MTHFR (methylenetetrahy-drofolate reductase) (C677T polymorphism) were the vari-ants which were not significantly associated with CAD andT2DM in this subgroup [88]
326 Genes Related to Diabetic Nephropathy All of 15 studiesin this subgroup were designed as case-control associationstudies [91ndash106] In 7 studies PCR-RFLP was used forgenotyping [92ndash95 99 102 103] in four studies PCRwas used[98 101 104 105] and in 4 of them both PCR and PCR-RFLPwere used [91 96 97 100]
Journal of Diabetes Research 15
Studying the association of 163AG polymorphism ofSUMO4 showed a positive significant association betweenAA carriers and diabetic nephropathy (119875 lt 005) [93]
Studying the interaction of eNOS4ab and G894Trevealed positive significant association between 4a or 894Tallele carriers and macro- and microalbuminuria (119875 = 001119875 = 002 resp) [91] It was observed that the interaction ofeNOS (G894T polymorphism) andACE (ID alleles) was sig-nificantly associated with more frequent macroalbuminuria(119875 = 0035) [97]
It has also been shown that interaction of eNOS (G894Tpolymorphisms) and MTHFR (C677T and A1298C poly-morphisms) eNOS T1298 C and eNOS T677 T carriershad positive significant association with macroalbuminuriaIn addition significant association of eNOS GT+TT carrierswith lipid profile (119875 lt 005) was shown in this study [99]
C677T andA1298C polymorphisms ofMTHFRwere alsoinvestigated in another study revealing that 677T 1298Cand 677T1298C carriers were significantly associated withmacroalbuminuria (119875 lt 0001) Positive significant asso-ciation when pooling CT+TT genotypes and 677T1298Cwas also found with microalbuminuria (119875 lt 0001) [103]Investigating the interaction of MTHFR (A1298C C677Tpolymorphisms) and ACE (ID alleles) showed a positivesignificant association of ACE D677T (119875 = 0035) and ACED1298C (119875 = 0012) genotypeswithmacroalbuminuria [96]
ACE (ID alleles) polymorphisms were investigated inthree studies In one study positive significant association(119875 lt 001) between DD carriers and progression but notdevelopment of albuminuria was observed [104] In anotherstudy in nephropathic subjects association of DD carriersand T2DM (119875 = 0006) but not nephropathy was revealed[105] However another study did not show significant asso-ciation of ACE with macroalbuminuria [98] Interaction ofACE (ID alleles) with Factor V Leiden (G1691A polymor-phism) was not significant [100]
Association of interleukins including IL-4 and IL-10 withdiabetic nephropathy was also investigated in two studiesStudy of minus592CA polymorphism of IL-10 revealed positivesignificant association between CC carriers and nephropathy(119875 = 0001) [94] and study ofminus590CTpolymorphismof IL-4revealed positive significant association between CT carriersand nephropathy (119875 lt 0001) [101]
Other significant associations between variants and dia-betic nephropathy included AT2R (angiotensin II recep-tor) (minus1332GA polymorphism) VEGF (vascular epitheliumgrowth factor) (+405GC polymorphism) and VDR (TaqIpolymorphism) [92 95 102] ApaI polymorphism of VDRwas not significantly associated with diabetic nephropathy[102]
327 Genes Related to Diabetic Retinopathy All of the 3studies in this subgroup were conducted as case-controlassociation studies [106ndash108]
Investigating nullpositive genotype of GSTM1 in a studywhich used ARMS-PCR for genotyping revealed that nullgenotype is significantly associated with diabetic retinopathy(119875 lt 005) [106] This result was confirmed in another study
by using multiplex PCR as genotyping [107] although nosignificant association between GSTT1 and retinopathy wasfound in this study [107]
Investigating +405GC polymorphism of VEGF alsorevealed positive significant association between GG carriersand diabetic retinopathy (119875 = 0005) [108]
328 Genes Related to Diabetic Foot Ulcer In this subgrouponly one study was found [109] which was case-controldesigned and used ARMS-PCR for genotyping In this studyassociation of minus7CT and minus2578CA polymorphisms ofVEGF with diabetic foot ulcer (DFU) was investigated and apositive significant association betweenAA carriers andDFU(119875 = 003) was observed But no significant association wasfound between minus7CT of VEGF and DFU [109]
4 Discussion
Diabetes mellitus is the eighth most frequent disease leadingcause of death throughout the world and now ranks the fifthfollowing communicable diseases cardiovascular diseasecancer and injuries [110] Prevalence of diabetes mellitus isincreasing worldwide [6]
Type 2 diabetes is the most frequent type of diabetesmellitus [110 111] Multiple genes and environmental factorsaffect the prevalence of T2DM Systematic review and meta-analysis studies have assessed the association between dif-ferent genes and T2DM Glutathione-S-transferase includingGSTMI GSTM1 and GSTP1 are important genes and theirassociation with diabetes has been investigated in two meta-analysis studies [112 113] It was revealed that null genotypeof both GSTM1 and GSTT1 could be as a risk factor fordiabetes while no significant association was found betweenGSTP1 and diabetes [112 113] These results are in linewith our finding and confirming the association of the nullgenotype of GSTT1 and GSTM1 with T2DM in Iranianpopulation [50] The relation between GSTT1 and GSTM1and diabetic retinopathy has also been shown in Iranianpopulation [106 107]
MTHFR is another important gene in association withT2DM and other related complications No associationof C677T polymorphism of MTHFR gene was found inAfricans Asians and Caucasians [114] MTHFR is a genewhich is involved in DNA methylation and synthesis andregulated folate activity It has been reported that mutanthomozygote and heterozygote of C677T polymorphism ofMTHFR increase plasma homocysteine which is an impor-tant factor leading to diabetic nephropathy (DN) and as aresult C677T polymorphism of MTHFR can be associatedwith the development of DN In Caucasians this associationhas also been observed [115] In Iranian population in linewith other populations no significant association was foundbetween MTHFR polymorphisms and T2DM [63] althoughsignificant association of 677T and 1298C alleles with diabeticnephropathy was observed [87] Interaction of two polymor-phisms and also interaction of MTHFR polymorphisms withother genes such as ACE and eNOS showed an associationwith development of DN [96 99]
16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
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Disease Markers
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OncologyJournal of
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Oxidative Medicine and Cellular Longevity
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Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
14 Journal of Diabetes Research
in another study positive significant association was foundbetween GC or CC carriers and T2DM (119875 = 0009) [64]
Adiponectin and its association with T2DM were inves-tigated in two studies [56 73] In one study two variantsincluding +45TG and minus11391GA were investigated but nosignificant relation was found between these two polymor-phisms and T2DM [56] However in another study investi-gating +45TG polymorphism of adiponectin it was revealedthat nonobese T2DM subjects had significantly higher TTgenotype (119875 = 004) [73]
In one study that investigated insulin receptor gene thefollowing mutations were found only in T2DM 511CgtA514TgtG 586 and 628TgtA on exon 2 694GgtC 680GgtA onexon 3 1627AgtT on exon 8 ATgtTG on intron 9 2007CgtCTon exon 9 2595CgtCT and 2669GgtCG on exon 13 2706 and2717CgtG 2752CgtT and 2753CgtG on exon 14 and 3471TgtAand 3516TgtG on exon 19 These mutations were not seen incontrol subjects [68]
Other variants which had significant association withT2DM included haptoglobin (allele 2-2) leptin (G-2548Apolymorphism) paraoxonase 2 (Ser311Cys polymorphism)GST (glutathione-S-transferase) M1 and GSTM1GSTT1interaction calpain-10 (SNP (single nucleotide polymor-phism) 43) IRS-1 (G972R polymorphism) and IRS-2(G1057D polymorphism) VDR (vitamin D receptor) (TaqIpolymorphism) KCNJ11 (E23K polymorphism) eNOS(endothelial nitric oxide synthase) VNTR (intron 4 ab pol-ymorphism) resistin (minus420CG polymorphism) and ACE(InsertionDeletion) [35ndash37 45 47 50 55 57 58 64 70]
In contrast to above variants CTLA4 (+49AG poly-morphism) HNF-1120572 (Ala98Val polymorphism) GLP-1R(glucagon-like peptid 1 receptor) (Thr149Met polymor-ohism) SLC30A8 (Arg325Trp polymorphism) GSTP1(Ile105Val polymorphism) glucokinase (minus30GA polymor-phism) SDF-1120573 (stromal derived factor -1 120573) (G801A poly-morphism) ApoE (apolipoprotein E) ENPP1 (ectoenzymenucleotide pyrophosphate phosphodiesterase 1) (K121Q poly-morphism) SUMO4 (small ubiquitin-like modifier 4)Met55Val polymorphism) MTHFR (C677T polymorphism)UCP2 (uncoupling protein 2) (minus866GA polymorphism)5HTTLPR IL-4 (minus590CT polymorphism) IFN-120574 (inter-feron 120574) (+874TA polymorphism) CCR5 (C-C chemokinereceptor type 5) (12057532mutation) HFE (hemochromatosisgene) (H63D C282Y PTPN1 (protein tyrosin Phosphatase1B)minus51delA minus451AgtG minus467TgtC minus1023CgtA minus1045GgtAminus1286 3 bp del ACA minus1291 9 bp del CTAGACTAA poly-morphisms) were not significantly associated with T2DM[22 42 46 50ndash52 54 59ndash63 66 67 71 74]
324 Genes Related to Insulin Resistance In this subgroupfour studies were assessed and all were designed as case-control association studies Three studies used PCR-RFL [7678 79] and one study used real-time PCR [77] for genotyping
The studies assessed in this subgroup showed a positiveassociation of TG carriers of +45TG polymorphism ofadiponectin (119875 = 0032) and Ala allele carriers of Pro12Alapolymorphism of PPAR120574 (119875 = 0036) with T2DM [76 77]A positive significant association of ff carriers of VDR wasalso shown (FokI polymorphism) (119875 = 002) and negative
association of 148insG carriers of PTPN1 (148insG polymor-phism) (119875 = 0041) with insulin resistance index [7879] However no significant association was shown betweenadiponectin receptor-2+795GA and T2DM [76]
325 Genes Related to Cardiovascular Disease in DiabetesDesign of all 11 studies in this subgroup was case-controlassociation study [80ndash84 86ndash90] except one study which wasdesigned as cross sectional [85] PCR-RFLP was used in all ofthem for genotyping [80ndash88 90] except in one study whichused ARMS-PCR method [89]
Paraoxonase 1 (163TA polymorphism) was the only vari-ant in this subgroup which was not significantly associatedwith atherosclerosis risk in T2DM [80] Investigation ofanother polymorphism of Paraoxonase 1 (Q192R) revealedthat diabetics with CAD had significant increase in RRgenotype (119875 lt 005) [81]
Investigating B1 and B2 alleles of CETP TaqI B allele in400 subjects showed that pooling of B1B1+B1B2 and B1B1genotypes had significant association with T2DM and CAD(119875 lt 001) On the other hand assessing the G894T poly-morphism of eNOS showed positive significant associationbetween TG and TT carriers and CAD (119875 lt 005) It was alsoshown that concomitant presence of NOS3 T allele and CEPTB1 allele was significantly associated with T2DM (119875 = 0004)and CAD (119875 = 0002) [83]
Investigation of apolipoprotein E (E2 E3 and E4) allelesshowed the association of E2 and E4 alleles with CAD(119875 lt 0001) [84 87] Also it was shown that interactionof butyrylcholinesterase (BChE K) and apolipoprotein E(ApoE) was associated significantly with CAD and diabetesApoE4BChE K had significant association with lipid profilesas well (119875 lt 005) [87]
Adiponectin +276GT and +45TG were significantlyassociated with CAD (119875 = 0023 and 0033 resp) [82] whileinvestigating minus1612 5A6A polymorphism of MMP-3 (matrixmetalloproteinase 3) showed a significant association withCAS (coronary artery stenosis) (119875 = 0008) [86]
In addition A1166C polymorphism of AT1R (angiotensinI receptor) and minus420CG polymorphism of resistin in dia-betic patients with CAD revealed significant association withdiabetes 119875 = 001 and 119875 = 0009 respectively [84 85]
Another study showed insertion(I)deletion(D) polymor-phismof angiotensin converting enzyme (ACE)DDgenotypewas significantly associated with higher blood pressure (119875 =0026) [89]
Factor V Leiden (G1691A polymorphism) prothrombin(G20210A polymorphism) and MTHFR (methylenetetrahy-drofolate reductase) (C677T polymorphism) were the vari-ants which were not significantly associated with CAD andT2DM in this subgroup [88]
326 Genes Related to Diabetic Nephropathy All of 15 studiesin this subgroup were designed as case-control associationstudies [91ndash106] In 7 studies PCR-RFLP was used forgenotyping [92ndash95 99 102 103] in four studies PCRwas used[98 101 104 105] and in 4 of them both PCR and PCR-RFLPwere used [91 96 97 100]
Journal of Diabetes Research 15
Studying the association of 163AG polymorphism ofSUMO4 showed a positive significant association betweenAA carriers and diabetic nephropathy (119875 lt 005) [93]
Studying the interaction of eNOS4ab and G894Trevealed positive significant association between 4a or 894Tallele carriers and macro- and microalbuminuria (119875 = 001119875 = 002 resp) [91] It was observed that the interaction ofeNOS (G894T polymorphism) andACE (ID alleles) was sig-nificantly associated with more frequent macroalbuminuria(119875 = 0035) [97]
It has also been shown that interaction of eNOS (G894Tpolymorphisms) and MTHFR (C677T and A1298C poly-morphisms) eNOS T1298 C and eNOS T677 T carriershad positive significant association with macroalbuminuriaIn addition significant association of eNOS GT+TT carrierswith lipid profile (119875 lt 005) was shown in this study [99]
C677T andA1298C polymorphisms ofMTHFRwere alsoinvestigated in another study revealing that 677T 1298Cand 677T1298C carriers were significantly associated withmacroalbuminuria (119875 lt 0001) Positive significant asso-ciation when pooling CT+TT genotypes and 677T1298Cwas also found with microalbuminuria (119875 lt 0001) [103]Investigating the interaction of MTHFR (A1298C C677Tpolymorphisms) and ACE (ID alleles) showed a positivesignificant association of ACE D677T (119875 = 0035) and ACED1298C (119875 = 0012) genotypeswithmacroalbuminuria [96]
ACE (ID alleles) polymorphisms were investigated inthree studies In one study positive significant association(119875 lt 001) between DD carriers and progression but notdevelopment of albuminuria was observed [104] In anotherstudy in nephropathic subjects association of DD carriersand T2DM (119875 = 0006) but not nephropathy was revealed[105] However another study did not show significant asso-ciation of ACE with macroalbuminuria [98] Interaction ofACE (ID alleles) with Factor V Leiden (G1691A polymor-phism) was not significant [100]
Association of interleukins including IL-4 and IL-10 withdiabetic nephropathy was also investigated in two studiesStudy of minus592CA polymorphism of IL-10 revealed positivesignificant association between CC carriers and nephropathy(119875 = 0001) [94] and study ofminus590CTpolymorphismof IL-4revealed positive significant association between CT carriersand nephropathy (119875 lt 0001) [101]
Other significant associations between variants and dia-betic nephropathy included AT2R (angiotensin II recep-tor) (minus1332GA polymorphism) VEGF (vascular epitheliumgrowth factor) (+405GC polymorphism) and VDR (TaqIpolymorphism) [92 95 102] ApaI polymorphism of VDRwas not significantly associated with diabetic nephropathy[102]
327 Genes Related to Diabetic Retinopathy All of the 3studies in this subgroup were conducted as case-controlassociation studies [106ndash108]
Investigating nullpositive genotype of GSTM1 in a studywhich used ARMS-PCR for genotyping revealed that nullgenotype is significantly associated with diabetic retinopathy(119875 lt 005) [106] This result was confirmed in another study
by using multiplex PCR as genotyping [107] although nosignificant association between GSTT1 and retinopathy wasfound in this study [107]
Investigating +405GC polymorphism of VEGF alsorevealed positive significant association between GG carriersand diabetic retinopathy (119875 = 0005) [108]
328 Genes Related to Diabetic Foot Ulcer In this subgrouponly one study was found [109] which was case-controldesigned and used ARMS-PCR for genotyping In this studyassociation of minus7CT and minus2578CA polymorphisms ofVEGF with diabetic foot ulcer (DFU) was investigated and apositive significant association betweenAA carriers andDFU(119875 = 003) was observed But no significant association wasfound between minus7CT of VEGF and DFU [109]
4 Discussion
Diabetes mellitus is the eighth most frequent disease leadingcause of death throughout the world and now ranks the fifthfollowing communicable diseases cardiovascular diseasecancer and injuries [110] Prevalence of diabetes mellitus isincreasing worldwide [6]
Type 2 diabetes is the most frequent type of diabetesmellitus [110 111] Multiple genes and environmental factorsaffect the prevalence of T2DM Systematic review and meta-analysis studies have assessed the association between dif-ferent genes and T2DM Glutathione-S-transferase includingGSTMI GSTM1 and GSTP1 are important genes and theirassociation with diabetes has been investigated in two meta-analysis studies [112 113] It was revealed that null genotypeof both GSTM1 and GSTT1 could be as a risk factor fordiabetes while no significant association was found betweenGSTP1 and diabetes [112 113] These results are in linewith our finding and confirming the association of the nullgenotype of GSTT1 and GSTM1 with T2DM in Iranianpopulation [50] The relation between GSTT1 and GSTM1and diabetic retinopathy has also been shown in Iranianpopulation [106 107]
MTHFR is another important gene in association withT2DM and other related complications No associationof C677T polymorphism of MTHFR gene was found inAfricans Asians and Caucasians [114] MTHFR is a genewhich is involved in DNA methylation and synthesis andregulated folate activity It has been reported that mutanthomozygote and heterozygote of C677T polymorphism ofMTHFR increase plasma homocysteine which is an impor-tant factor leading to diabetic nephropathy (DN) and as aresult C677T polymorphism of MTHFR can be associatedwith the development of DN In Caucasians this associationhas also been observed [115] In Iranian population in linewith other populations no significant association was foundbetween MTHFR polymorphisms and T2DM [63] althoughsignificant association of 677T and 1298C alleles with diabeticnephropathy was observed [87] Interaction of two polymor-phisms and also interaction of MTHFR polymorphisms withother genes such as ACE and eNOS showed an associationwith development of DN [96 99]
16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
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Computational and Mathematical Methods in Medicine
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
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Gastroenterology Research and Practice
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Journal of Diabetes Research 15
Studying the association of 163AG polymorphism ofSUMO4 showed a positive significant association betweenAA carriers and diabetic nephropathy (119875 lt 005) [93]
Studying the interaction of eNOS4ab and G894Trevealed positive significant association between 4a or 894Tallele carriers and macro- and microalbuminuria (119875 = 001119875 = 002 resp) [91] It was observed that the interaction ofeNOS (G894T polymorphism) andACE (ID alleles) was sig-nificantly associated with more frequent macroalbuminuria(119875 = 0035) [97]
It has also been shown that interaction of eNOS (G894Tpolymorphisms) and MTHFR (C677T and A1298C poly-morphisms) eNOS T1298 C and eNOS T677 T carriershad positive significant association with macroalbuminuriaIn addition significant association of eNOS GT+TT carrierswith lipid profile (119875 lt 005) was shown in this study [99]
C677T andA1298C polymorphisms ofMTHFRwere alsoinvestigated in another study revealing that 677T 1298Cand 677T1298C carriers were significantly associated withmacroalbuminuria (119875 lt 0001) Positive significant asso-ciation when pooling CT+TT genotypes and 677T1298Cwas also found with microalbuminuria (119875 lt 0001) [103]Investigating the interaction of MTHFR (A1298C C677Tpolymorphisms) and ACE (ID alleles) showed a positivesignificant association of ACE D677T (119875 = 0035) and ACED1298C (119875 = 0012) genotypeswithmacroalbuminuria [96]
ACE (ID alleles) polymorphisms were investigated inthree studies In one study positive significant association(119875 lt 001) between DD carriers and progression but notdevelopment of albuminuria was observed [104] In anotherstudy in nephropathic subjects association of DD carriersand T2DM (119875 = 0006) but not nephropathy was revealed[105] However another study did not show significant asso-ciation of ACE with macroalbuminuria [98] Interaction ofACE (ID alleles) with Factor V Leiden (G1691A polymor-phism) was not significant [100]
Association of interleukins including IL-4 and IL-10 withdiabetic nephropathy was also investigated in two studiesStudy of minus592CA polymorphism of IL-10 revealed positivesignificant association between CC carriers and nephropathy(119875 = 0001) [94] and study ofminus590CTpolymorphismof IL-4revealed positive significant association between CT carriersand nephropathy (119875 lt 0001) [101]
Other significant associations between variants and dia-betic nephropathy included AT2R (angiotensin II recep-tor) (minus1332GA polymorphism) VEGF (vascular epitheliumgrowth factor) (+405GC polymorphism) and VDR (TaqIpolymorphism) [92 95 102] ApaI polymorphism of VDRwas not significantly associated with diabetic nephropathy[102]
327 Genes Related to Diabetic Retinopathy All of the 3studies in this subgroup were conducted as case-controlassociation studies [106ndash108]
Investigating nullpositive genotype of GSTM1 in a studywhich used ARMS-PCR for genotyping revealed that nullgenotype is significantly associated with diabetic retinopathy(119875 lt 005) [106] This result was confirmed in another study
by using multiplex PCR as genotyping [107] although nosignificant association between GSTT1 and retinopathy wasfound in this study [107]
Investigating +405GC polymorphism of VEGF alsorevealed positive significant association between GG carriersand diabetic retinopathy (119875 = 0005) [108]
328 Genes Related to Diabetic Foot Ulcer In this subgrouponly one study was found [109] which was case-controldesigned and used ARMS-PCR for genotyping In this studyassociation of minus7CT and minus2578CA polymorphisms ofVEGF with diabetic foot ulcer (DFU) was investigated and apositive significant association betweenAA carriers andDFU(119875 = 003) was observed But no significant association wasfound between minus7CT of VEGF and DFU [109]
4 Discussion
Diabetes mellitus is the eighth most frequent disease leadingcause of death throughout the world and now ranks the fifthfollowing communicable diseases cardiovascular diseasecancer and injuries [110] Prevalence of diabetes mellitus isincreasing worldwide [6]
Type 2 diabetes is the most frequent type of diabetesmellitus [110 111] Multiple genes and environmental factorsaffect the prevalence of T2DM Systematic review and meta-analysis studies have assessed the association between dif-ferent genes and T2DM Glutathione-S-transferase includingGSTMI GSTM1 and GSTP1 are important genes and theirassociation with diabetes has been investigated in two meta-analysis studies [112 113] It was revealed that null genotypeof both GSTM1 and GSTT1 could be as a risk factor fordiabetes while no significant association was found betweenGSTP1 and diabetes [112 113] These results are in linewith our finding and confirming the association of the nullgenotype of GSTT1 and GSTM1 with T2DM in Iranianpopulation [50] The relation between GSTT1 and GSTM1and diabetic retinopathy has also been shown in Iranianpopulation [106 107]
MTHFR is another important gene in association withT2DM and other related complications No associationof C677T polymorphism of MTHFR gene was found inAfricans Asians and Caucasians [114] MTHFR is a genewhich is involved in DNA methylation and synthesis andregulated folate activity It has been reported that mutanthomozygote and heterozygote of C677T polymorphism ofMTHFR increase plasma homocysteine which is an impor-tant factor leading to diabetic nephropathy (DN) and as aresult C677T polymorphism of MTHFR can be associatedwith the development of DN In Caucasians this associationhas also been observed [115] In Iranian population in linewith other populations no significant association was foundbetween MTHFR polymorphisms and T2DM [63] althoughsignificant association of 677T and 1298C alleles with diabeticnephropathy was observed [87] Interaction of two polymor-phisms and also interaction of MTHFR polymorphisms withother genes such as ACE and eNOS showed an associationwith development of DN [96 99]
16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
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16 Journal of Diabetes Research
Interleukins especially IL-10 are shown to have significantassociation with T2DM in different ethnic groups Significantassociation between minus592CA and minus819CT polymorphismsof IL-10 and T2DM risk in Africans was shown [116] Alsominus1082AGpolymorphismof IL-10 seems to be a risk factor forT2DM in Asians but not in Europeans and Africans [116] Inanother study it was reported that minus1082GG genotype of IL-10 and minus174CC genotype of IL-6 are as risk factors for T2DMin Egyptians [117] In our study IL-4 has been studied but nosignificant association with T2DM was seen [66]
Investigation of different polymorphisms of adiponectinand their association with T2DM in a meta-analysis studyrevealed minus11391GgtA and minus11426AgtG polymorphisms ofadiponectin as risk factor for T2DM in Europeans andminus11377CgtG variant of adiponectin as risk factor of T2DM inEuropeans and Asians [110] It was also shown that +45TgtGand +276GgtT variants are not associated with T2DM inEuropeans Africans andAsians [110] In contrast to previousstudies +45TgtG and minus11391GgtA polymorphisms were notassociated with T2DM in this study due to difference ingenetic background [56]
Among candidate genes in association with T2DMTCF7L2 is one of the strongest genes related to diabetesIn a meta-analysis study after pooling all data of EuropeanAfrican and Asian populations it has been revealed thatrs12255372 polymorphism of TCF7L2 significantly increasesthe risk of T2DM However no data from Iranian populationas a type of Asian population was included in this meta-analysis [111] In line with these data in our study we founda positive association between rs12255372 and rs7903146variants of TCF7L2 and T2DM [38 48 53]
Pro12Ala polymorphism of PPAR120574 is found to be as aprotective variant especially in Asian population althoughthe results were highly heterogeneous [118] In our study theresults were controversial In one study no association wasfound between this polymorphism and T2DM in contrastwith previous studies [69] while in other studies protectiveeffect of this polymorphism with T2DM was confirmed inline with previous studies [41 75] These controversial datamay be due to different ethnicity in different populationsbeing studied in Iran Small sample size could be anotherreason for the controversial results
Type 1 diabetes mellitus is another type of diabetesin which HLA (human lymphocyte antigen) IR1R1 (inter-leukin-1 receptor type 1) CTLA-4 and VDR are some impor-tant genes studied in association with T1DM [119] VDR isone of the most studied genes in relation to T1DM due to itsrole in T-cell mediated autoimmune diseases [119 120]Meta-analysis studies showed that BsmI and FokI polymorphismsof VDR increased the risk of T1DM in East and West Asiansrespectively [119] In our study controversial results werefound In one study BsmI was shown to be associated withT1DM [25] while in another study no association was found[26] FokI was not associated with T1DM in our study incontrast to previous studies which might be due to differencein ethnicity and genetic background or insufficient clinicaldata [25 26]
Among diabetic complications CAD and DN are themost studied complications Meta-analysis studies showed
that rs2010963 and rs3025039 polymorphisms of VEGF 4baT-786C and G894T polymorphisms of eNOS and ACEare associated with DN [121ndash123] In our study 4ab andG894T polymorphisms of eNOS and ACE were shown to beassociatedwithDN in linewith previous studies [91 104 105]In our study rs2010963 polymorphism of VEGF was alsofound to be associated with diabetic nephropathy which wasin line with previous studies [95]
The most investigated genes in association with CADinclude PPAR120574 TCF7L2 ACE TNF-120572 adiponectin and IRS1[118] In our study +45TgtG and +276GgtT polymorphisms ofadiponectin were investigated and the significant associationof these variants with CAD was confirmed [82]
Overall it seems that more studies are needed to identifydiabetes susceptibility genes in Iranian population Investi-gation of candidate genes is one way to understand thesegenes but the method with the least expenses and erroris GWAS which scans a set of loci in association with adisease in many people GWAS in different populations suchas Americans Caucasians Australians West Africans andEuropeans revealed multiple loci in association with T2DM[124ndash128] In Asians especially in Middle Eastern countriesGWAS is critically needed In our investigations we reviewedfive studieswhich investigated the association between eNOSACE MTHFR and factor V Leiden and the interactionbetween them and diabetic nephropathy and reach a coherentresult [91 97 99 100 104] while GWAS could be helpful andreduce time and other expenses [126]
However there are some strength and some limitationsin our study Firstly this systematic review for the first timeassessed the association between genetic variants and dia-betes in Iranian population Moreover the studies includedin this systematic review were assessed for quality andselected as high quality (scored ge 3) For limitations it shouldbe considered that all included studies were observationalwhich does not allow reliable inferences about causalityMoreover due to methodological heterogeneity we were notable to pool the data and perform the meta-analysis
5 Conclusion
Our study showed significant association between CTLA-4 IL-18 VDR TAP2 IL-12 and CD4 genes and T1DMHNF120572 gene had significant association with MODY Thefollowing genes showed significant association with T2DMhaptoglobin paraoxonase leptin TCF7L2 calreticulin ER120572PPAR-1205742 CXCL5 calpain-10 IRS-1 and 2 GSTM1 KCNJ11eNOS VDR resistin INSR ACE ApoA-I adiponectin andPTPN1 In assessment of association between CAD anddiabetes in Iranian population the following genes showedsignificant association paraoxonase 1 adiponectin eNOSCETP AT1R resistin MMP-3 BChE K Apo E ACE Thefollowing genes had significant association with diabeticnephropathy eNOS AT2R SUMO4 IL-10 VEGF MTHFRACE and VDR The following genes had significant associ-ation with diabetic retinopathy GSTM1 and VEGF and alsoVEGF had significant association with diabetic foot ulcer
Insufficient data might cause the conflicting resultsthereforeGWAS on defined populationwith large sample size
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Journal of Diabetes Research 17
is suggested as a more comprehensive approach answeringmany more questions
Conflict of Interests
The authors declare that they have no conflict of interests
References
[1] American Diabetes Association ldquoDiagnosis and classificationof diabetes mellitusrdquo Diabetes Care vol 27 Supplement 1 ppS5ndashS10 2004
[2] World Health Organization (WHO) Diabetes Mellitus Reportof aWHOExpert CommitteeWHOTechnical Report Series no310 World Health Organization Geneva Switzerland 1965
[3] World Health Organization (WHO) ldquoWHO expert committeeon diabetes mellitusrdquo WHO Technical Report Series No 646WorldHealthOrganization (WHO)Geneva Switzerland 1980
[4] International Diabetes Federation IDF Diabetes Atlas Inter-national Diabetes Federation 6th edition 2013 httpwwwidforgdiabetesatlas
[5] F Najafipoor F Azizi and M Zareizadeh ldquoEpidemiologicinvestigation of familial type 2 diabetes in Tehranrdquo Iranian Jour-nal of Diabetes and Lipid Disorders vol 4 no 1 pp 35ndash42 2004
[6] IDF Diabetes Atlas New Estimates for 2012 of Diabetes Preva-lence Mortality and Healthcare Expenditures 5th edition 2012httpwwwidforg
[7] A A Haghdoost M Rezazadeh-Kermani B Sadghirad andH R Baradaran ldquoPrevalence of type 2 diabetes in the IslamicRepublic of Iran systematic review and meta-analysisrdquo EasternMediterranean Health Journal vol 15 no 3 pp 591ndash599 2009
[8] S M Akrami ldquoGenetic counseling in diabetesrdquo Iranian Journalof Diabetes and Lipid Disorders vol 6 no 3 pp 205ndash213 2007
[9] National Diabetes Data Group ldquoClassification and diagnosis ofdiabetes mellitus and other categories of glucose intolerancerdquoDiabetes vol 28 no 12 pp 1039ndash1057 1979
[10] K Xiang Y Wang T Zheng et al ldquoGenome-wide searchfor type 2 diabetesimpaired glucose homeostasis susceptibilitygenes in the Chineserdquo Diabetes vol 59 pp 228ndash234 2004
[11] T H Luo Y Zhao G Li et al ldquoA genome-wide search for typeII diabetes susceptibility genes in Chinese Hansrdquo Diabetologiavol 44 no 4 pp 501ndash506 2001
[12] O Ali ldquoGenetics of type 2 diabetesrdquoWorld Journal of Diabetesvol 4 no 4 pp 114ndash123 2013
[13] I Prokopenko M I McCarthy and C M Lindgren ldquoType 2diabetes new genes new understandingrdquo Trends in Geneticsvol 24 no 12 pp 613ndash621 2008
[14] SAbbas S T Raza FAhmedAAhmad S Rizvi andFMahdildquoAssociation of genetic polymorphism of PPAR120574-2 ACEMTHFR FABP-2 and FTO genes in risk prediction of type 2diabetes mellitusrdquo Journal of Biomedical Science vol 20 no 1pp 80ndash88 2013
[15] Q-Y Huang M-R Cheng and S-L Ji ldquoLinkage and associa-tion studies of the susceptibility genes for type 2 diabetesrdquo ActaGenetica Sinica vol 33 no 7 pp 573ndash589 2006
[16] S Li H J Shin E L Ding and R M van Dam ldquoAdiponectinlevels and risk of type 2 diabetes a systematic review and meta-analysisrdquo The Journal of the American Medical Association vol302 no 2 pp 179ndash188 2009
[17] S Bakhtiari A Babakhani M H Maleki et al ldquoInvestigationof the association between rs2970847 polymorphism of PGC-1120572 gene and type 2 diabetes mellitus a systematic review andmeta analysisrdquo Journal of Research of Medical School of ShahidBeheshti University vol 36 pp 104ndash110 2012
[18] H Ounissi-Benkalha and C Polychronakos ldquoThe moleculargenetics of type 1 diabetes new genes and emerging mecha-nismsrdquoTrends inMolecularMedicine vol 14 no 6 pp 268ndash2752008
[19] D Moher A Liberati J Tetzlaff and D G Altman ldquoPreferredreporting items for systematic reviews and meta-analyses thePRISMA statementrdquo BritishMedical Journal vol 339 Article IDb2535 2009
[20] World Health Organization (WHO) ldquoDefinition and diagnosisof diabetes mellitusand intermediate hyperglycemiardquo Report ofa WHOIDF Consultation 2006
[21] J P Vandenbroucke E von Elm D G Altman et al ldquoStrength-ening the reporting of observational studies in epidemiology(STROBE) explanation and elaborationrdquo PLoSMedicine vol 4no 10 article e297 2007
[22] S Ahmadi J Rostamzadeh D Khosravi P Shariati and NShakiba ldquoAssociation of CTLA-4 gene 49AG polymorphismwith the incidence of type 1 diabetes mellitus in the IranianKurdish populationrdquo Pakistan Journal of Biological Sciences vol16 no 24 pp 1929ndash1935 2013
[23] Z Karamizadeh E Kamali Sarvestani F Saki et al ldquoInvestiga-tion of osteopontin levels and genomic variation of osteopontinand its receptors in type 1 diabetes mellitusrdquo Journal of Endo-crinological Investigation vol 36 no 11 pp 1090ndash1093 2013
[24] M Rahbani-Nabar A Rezaie S Bazzaz and N A ZadehldquoAssociation of 137 polymorphism in the interleukin-18 genepromoter with diabetes melhitus type 1 in East Azerbaijan pop-ulationrdquoMedical Journal of Tabriz University ofMedical Sciencesand Health Services vol 35 no 2 pp 38ndash43 2013
[25] S Bonakdaran M R Abbaszadegan E Dadkhah and MKhajeh-Dalouie ldquoVitamin D receptor gene polymorphisms intype 1 diabetes mellitus a new pattern fromKhorasan provinceIslamicRepublic of IranrdquoEasternMediterraneanHealth Journalvol 18 no 6 pp 614ndash619 2012
[26] Z Mohammadnejad M Ghanbari R Ganjali et al ldquoAssocia-tion between vitamin D receptor gene polymorphisms and type1 diabetes mellitus in Iranian populationrdquo Molecular BiologyReports vol 39 no 2 pp 831ndash837 2012
[27] J T Afshari S M Taghavi S S Fatemi H Rafatpanah FGheybi and N Nezamdoost ldquoTAP2 polymorphisms in Iranianpatients with type I diabetes mellitusrdquo International Journal ofGenetics and Molecular Biology vol 3 no 8 pp 115ndash119 2011
[28] A Massoud N Sheikh Bahai M Massoud et al ldquoIL18 genepolymorphism in type I diabetic patients a case-control studyrdquoTehranUniversityMedical Journal vol 67 no 1 pp 20ndash24 2009
[29] MMasood I SalehiN SheykhBahayiMVojgani AA Rajaband A Massoud ldquoInvestigation of codon 25 polymorphismof TGF120573 gene in type I diabetes mellitus patientsrdquo Journal ofMedical Faculty Guilan University of Medical Sciences vol 16no 62 pp 1ndash6 2007
[30] A H Masoud A Keihani N Sheykhbahaee et al ldquoInvesti-gation of polymorphism of IL-12 in type I diabetes mellituspatientsrdquo Medical Journal of Mashhad University of MedicalSciences vol 50 no 97 pp 283ndash286 2007
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
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Diabetes ResearchJournal of
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Research and TreatmentAIDS
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Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
18 Journal of Diabetes Research
[31] Z Mojtahedi S Naeimi S Farjadian G R Omrani and AGhaderi ldquoAssociation of IL-18 promoter polymorphisms withpredisposition to Type 1 diabetesrdquoDiabeticMedicine vol 23 no3 pp 235ndash239 2006
[32] Z Mojtahedi G R Omrani M Doroudchi and A GhaderildquoCTLA-4 +49 AG polymorphism is associated with predis-position to type 1 diabetes in Iraniansrdquo Diabetes Research andClinical Practice vol 68 no 2 pp 111ndash116 2005
[33] M Zamani M A Tabatabaiefar A S Esfahani F MostafaviA Sotoudeh and B Larijani ldquoCorrelation between the CD4gene polymorphism with type 1 diabetes mellitus in the Iranianpopulationrdquo Iranian Journal of Diabetes and LipidDisorders vol4 no 4 pp 1ndash9 2005
[34] SM Taghavi S S Fatemi H Rafatpanah R Ganjali J Tavako-lafshari and N Valizadeh ldquoMutations in the coding regionsof the hepatocyte nuclear factor 4 alpha in Iranian familieswith maturity onset diabetes of the youngrdquo CardiovascularDiabetology vol 8 article 63 2009
[35] A A Amiri M B Hashemi-Soteh M R Haghshenas FDaneshvar A Rastegar and T Farazmand ldquoHaptoglobin poly-morphism in individuals with type 2 diabeticmicroangiopathyrdquoNorth American Journal of Medical Sciences vol 5 no 9 pp529ndash535 2013
[36] S Andalib G Vaseghi A Motavallian et al ldquoAssociation ofpolymorphism of ser311cys paraoxonase-2 gene with type 2diabetes mellitus in Iranrdquo International Journal of PreventiveMedicine vol 4 no 5 pp 517ndash522 2013
[37] L Kohan M Nasiri A Habib and A Bolhasani ldquoAssociationof G-2548A polymorphism in the promoter of leptin gene withplasma leptin level and risk of type 2 diabetesrdquo Journal of ShahidSadoughi University of Medical Sciences vol 21 no 1 pp 70ndash772013
[38] F M Alami N M Samaei M Ahmadi et al ldquoAssociation oftranscription factor 7-like 2 (Tcf7l2) gene haplotypes with therisk of type 2 diabetes mellitus in Iranrdquo Advances in BiologicalResearch vol 7 no 5 pp 145ndash150 2013
[39] S Mahmazi K Parivar M Rahnema and M Ohadi ldquoCalretic-ulin novel mutations in type 2 diabetes mellitusrdquo InternationalJournal of Diabetes in Developing Countries vol 33 no 4 pp219ndash225 2013
[40] F Mohammadi M Pourahmadi M Mosalanejad H JamaliM A Ghobadifar and S Erfanian ldquoAssociation of estrogenreceptor 120572 genes PvuII and XbaI polymorphisms with type 2diabetes mellitus in the inpatient population of a hospital inSouthern Iranrdquo Diabetes and Metabolism Journal vol 37 no 4pp 270ndash277 2013
[41] A Motavallian S Andalib G Vaseghi H Mirmohammad-Sadeghi and M Amini ldquoAssociation between PRO12ALApolymorphismof the PPAR-1205742 gene and type 2 diabetesmellitusin Iranian patientsrdquo Indian Journal of Human Genetics vol 19no 2 pp 239ndash244 2013
[42] S Sepahi R Jalal B Toluinia A Asoodeh and J DarvishldquoEvaluation of relationship between HNF-1120572 and GLP-1R poly-morphisms and type 2 diabetes in a population living innortheast of Iranrdquo Journal of Cell and Molecular Research vol5 no 2 pp 54ndash59 2013
[43] M H Sheikhha M Afkhami-Ardekani S M R Mirjalili S MR Dehghani and H R Ghadimi ldquoInvestigating the frequencyof MSPI polymorphism of APOA1 gene in type II diabeticpatients and comparing it with this frequency in nondiabeticsrdquoGenetics in the 3rd Millennium vol 11 no 2 pp 3078ndash30832013
[44] H Yaghoubi M Haghi and S Solhi ldquoDetection of CXCL5 genepolymorphism with diabetes in Ardabil provincerdquo Journal ofArdabil University of Medical Sciences vol 13 no 4 pp 438ndash443 2013
[45] F Bahreini S M M Ardebili S Farajnia et al ldquoA study onassociation of SNP-43 polymorphism in Calpain-10 gene withtype 2 diabetes mellitus in the population of Eastern Azerbaijanprovincerdquo Iranian SouthMedical of Journal vol 15 no 1 pp 35ndash41 2012
[46] R Derakhshan M K Arababadi Z Ahmadi et al ldquoIncreasedcirculating levels of SDF-1 (CXCL12) in type 2 diabetic patientsare correlated to disease state but are unrelated to polymor-phism of the SDF-1120573 gene in the Iranian populationrdquo Inflam-mation vol 35 no 3 pp 900ndash904 2012
[47] K Haghani and S Bakhtiyari ldquoThe study on the relationshipbetween IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymor-phisms and type 2 diabetes in the Kurdish ethnic group in westIranrdquo Genetic Testing and Molecular Biomarkers vol 16 no 11pp 1270ndash1276 2012
[48] F M Alami M Ahmadi H Bazrafshan et al ldquoAssociationof the TCF7L2 rs12255372 (GT) variant with type 2 diabetesmellitus in an Iranian populationrdquo Genetics and MolecularBiology vol 35 no 2 pp 413ndash417 2012
[49] R Meshkani H Saberi N Mohammadtaghvaei and M ATabatabaiefar ldquoEstrogen receptor alpha gene polymorphismsare associated with type 2 diabetes and fasting glucose in malesubjectsrdquoMolecular and Cellular Biochemistry vol 359 no 1-2pp 225ndash233 2012
[50] E Moasser S R Kazemi-Nezhad M Saadat and N AzarpiraldquoStudy of the association between glutathione S-transferase(GSTM1 GSTT1 GSTP1) polymorphisms with type II diabetesmellitus in southern of IranrdquoMolecular Biology Reports vol 39no 12 pp 10187ndash10192 2012
[51] S M Mohaddes F Karami J Gharesouran and A BahramildquoThe soluble carrier 30 A8 (SLC30A8) gene polymorphism andrisk ofDiabetesMellitus Type 2 in EasternAzerbijan populationof Iranrdquo Journal of Sciences Islamic Republic of Iran vol 23 no1 pp 15ndash20 2012
[52] M R Oladi J Behravan M Hassani et al ldquoGlucokinase genepromoter-30GgtA polymorphism a cross-sectional associationstudy with obesity diabetesMellitus hyperlipidemia hyperten-sion andmetabolic syndrome in an Iranian hospitalrdquo Revista deNutricao vol 25 no 4 pp 487ndash495 2012
[53] A Palizban M Nikpour R Salehi and M-R Maracy ldquoAssoci-ation of a common variant in TCF7L2 gene with type 2 diabetesmellitus in a Persian populationrdquo Clinical and ExperimentalMedicine vol 12 no 2 pp 115ndash119 2012
[54] O Tabatabaei-Malazy H Fakhrzadeh M Qorbani et alldquoApolipoprotein E gene polymorphism and its effect on anthro-pometric measures in normoglycemic subjects and type 2diabetesrdquo Journal of Diabetes amp Metabolic Disorders vol 11article 18 2012
[55] M Ghasemi R Habibipour and P Keshavarz ldquoThe associationstudy of the E23k Kcnj11 variant with progression of type 2diabetes among obese individuals in a population in the Northof Iranrdquo Iranian Journal of Endocrinology and Metabolism vol13 supplement 6 pp S673ndashS680 2012
[56] SH RanjbarMMAmoliM Sajadi et al ldquoGenetic associationanalysis of the adiponectin polymorphisms in type 2 diabeteswith and without complicationsrdquo Iranian Journal of Diabetesand Lipid Disorders vol 10 pp 1ndash4 2011
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
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Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Journal of Diabetes Research 19
[57] M Mehrab-Mohseni O Tabatabaei-Malazy S Hasani-Ranjbaret al ldquoEndothelial nitric oxide synthase VNTR (intron 4 ab)polymorphism association with type 2 diabetes and its chroniccomplicationsrdquo Diabetes Research and Clinical Practice vol 91no 3 pp 348ndash352 2011
[58] RNosratabadiM K Arababadi andVA Salehabad ldquoVitaminD receptor polymorphisms in type 2 diabetes in southeasternIranian patientsrdquo Laboratory Medicine vol 42 no 1 pp 32ndash342011
[59] H Saberi NMohammadtaghvaei S Gulkho et al ldquoThe ENPP1K121Q polymorphism is not associated with type 2 diabetes andrelatedmetabolic traits in an Iranian populationrdquoMolecular andCellular Biochemistry vol 350 no 1-2 pp 113ndash118 2011
[60] S Fallah M Jafarzadeh and M Hedayati ldquoNo association ofthe SUMO4 polymorphism M55V variant in type 2 diabetes inIranian subjectsrdquo Diabetes Research and Clinical Practice vol90 no 2 pp 191ndash195 2010
[61] J Heidari S M Akrami R Heshmat P Amiri H FakhrzadehandM Pajouhi ldquoAssociation study of the minus866GA UCP2 genepromoter polymorphism with type 2 diabetes and obesity in atehran population a case control studyrdquo Archives of IranianMedicine vol 13 no 5 pp 384ndash390 2010
[62] H Nazem M A Takhshid S M B Tabei F Sholevar MEntezam and J Manoochehri ldquoInvestigation of associationbetween serotonin transporter gene and type 2 diabetes melli-tusrdquo Iranian Journal of Diabetes and Lipid Disorders vol 10 no1 pp 84ndash89 2010
[63] J T Bazzaz M Shojapoor H Nazem et al ldquoMethylenetetra-hydrofolate reductase gene polymorphism in diabetes and obe-sityrdquoMolecular Biology Reports vol 37 no 1 pp 105ndash109 2010
[64] S Emamgholipour AHossein-nezhadANajmafsharM Rah-mani and B Larijani ldquoPromoter resistin gene polymorphismin patients with type 2 diabetes and its influence on concernedmetabolic phenotypesrdquo Iranian Journal of Diabetes and LipidDisorders vol 8 no 1 pp 150ndash156 2009
[65] S Hasani-Ranjbar P Amiri M Namakchian et al ldquoInvestiga-tion of association between CXCL5 gene polymorphism anddiabetesrdquo Iranian Journal of Diabetes and Lipid Disorders vol8 no 3 pp 247ndash252 2009
[66] M Kazemi Arababadi A A Pourfathollah S Daneshmandi etal ldquoEvaluation of relation between IL-4 and IFN-120574 polymor-phisms and type 2 diabetesrdquo Iranian Journal of Basic MedicalSciences vol 12 no 2 pp 100ndash104 2009
[67] M K Arababadi N Naghavi G Hassanshahi and M SajadildquoEvaluating the association of CCR5-d32 mutation with type2 diabetes in Rafsanjanese patientsrdquo Feyz Journal of KashanUniversity of Medical Sciences vol 13 no 3 pp 208ndash213 2009
[68] B Kazemi N Seyed E Moslemi et al ldquoInsulin receptor genemutations in Iranian patients with type II diabetes mellitusrdquoIranian Biomedical Journal vol 13 no 3 pp 161ndash168 2009
[69] H Mirzaei S M Akrami T Golmohammadi et al ldquoPoly-morphism of Pro12Ala in the peroxisome proliferator-activatedreceptor 2 gene in Iranian diabetic and obese subjectsrdquo Meta-bolic Syndrome and Related Disorders vol 7 no 5 pp 453ndash4582009
[70] A Nikzamir M Nakhjavani T Golmohammadi L Dibaiand R Saffary ldquoPolymorphism in the angiotensin-convertingenzyme (ACE) gene and ACE activity in type 2 diabeticpatientsrdquo Acta Medica Iranica vol 46 no 4 pp 277ndash282 2008
[71] F Sharifi A Esmaeilzadeh and M Zali ldquoHemochromatosisgene (HFE) mutations in patients with type 2 diabetes and theircontrol group in an Iranian populationrdquo Saudi Medical Journalvol 29 no 6 pp 808ndash812 2008
[72] A Besharati S M Akrami R Heshmat P Yaghmaee and BAlirezapoor ldquoInvestigation of association between apoAI genepolymorphisms and lipid profiles and type 2 diabetesmellitus inIranian populationrdquo Journal of Islamic Republic of Iran MedicalCouncil vol 25 no 2 pp 132ndash141 2007
[73] S Hasani-Ranjbar J Tavakkoly Bazzaz P Amiri M M Amoliand B Larijani ldquoInvestigation of the frequency of +45TGpolymorphismof adiponectin gene in type 2 diabetic patients ina Tehranian populationrdquo Iranian Journal of Diabetes and LipidDisorders vol 6 no 3 pp 215ndash218 2007
[74] R Meshkani M Taghikhani H Al-Kateb et al ldquoPolymor-phisms within the protein tyrosine phosphatase IB (PTPN1)gene promoter functional characterization and associationwith type 2 diabetes and related metabolic traitsrdquo ClinicalChemistry vol 53 no 9 pp 1585ndash1592 2007
[75] R Meshkani M Taghikhani B Larijani et al ldquoPro12Ala poly-morphism of the peroxisome proliferator-activated receptor-1205742(PPAR120574-2) gene is associated with greater insulin sensitivityand decreased risk of type 2 diabetes in an Iranian populationrdquoClinical Chemistry and Laboratory Medicine vol 45 no 4 pp477ndash482 2007
[76] F Namvaran M-P Rahimi N Azarpira and M H Dab-baghmanesh ldquoPolymorphism of adiponectin (45TG) andadiponectin receptor-2 (795GA) in an iranian populationrelation with insulin resistance and response to treatment withpioglitazone in patientswith type 2 diabetesmellitusrdquoMolecularBiology Reports vol 39 no 5 pp 5511ndash5518 2012
[77] F Namvaran N Azarpira P Rahimi-Moghaddam and M HDabbaghmanesh ldquoPolymorphism of peroxisome proliferator-activated receptor 120574 (PPAR120574) Pro12Ala in the Iranian popula-tion Relation with insulin resistance and response to treatmentwith pioglitazone in type 2 diabetesrdquo European Journal ofPharmacology vol 671 no 1ndash3 pp 1ndash6 2011
[78] A Hossein-nezhad K Mirzaei P Shabani et al ldquoAssociationof VDR gene polymorphism with insulin resistance in diabeticpatientrsquos running title VDR and insulin resistancerdquo IranianJournal of Diabetes and Lipid Disorders vol 8 no 1 pp 143ndash1492009
[79] A Moosapoor M Taghikhani R Meshkani S Khatami SBakhtiari and K Haghani ldquoAssociation of 31015840UTR (1484insG)polymorphism of PTP1B gene with Type 2 diabetes in-sulinresistance and obesity in a Tehranian populationrdquo Journal ofSchool of Public Health and Institute of Public Health Researchvol 5 no 3 pp 1ndash13 2007
[80] R BayatmakooHMobaiyen AMonfaredan K B Sofiani andR Benissy ldquoThe study of effects common paraoxonase poly-morphism (L55M) on atherosclerosis risk in diabetic patientsby PCR-RFLPrdquo European Journal of Experimental Biology vol3 no 3 pp 512ndash516 2013
[81] R Bayatmakoo A Monfaredan N Bargahi H Mobaiyen andN Aslanabadi ldquoParaoxonase gene polymorphism and athero-sclerosis risk in diabetic patientsrdquo Journal of Azad University ofMedical Sciences vol 22 no 3 pp 191ndash197 2012
[82] A Esteghamati N Mansournia M Nakhjavani M A Man-sournia A Nikzamir and M Abbasi ldquoAssociation of +45(TG)and +276(GT) polymorphisms in the adiponectin gene withcoronary artery disease in a population of Iranian patients withtype 2 diabetesrdquo Molecular Biology Reports vol 39 no 4 pp3791ndash3797 2012
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
20 Journal of Diabetes Research
[83] Z Rahimi R Nourozi-Rad and A Parsian ldquoStrong interactionbetween T allele of endothelial nitric oxide synthase with B1allele of cholesteryl ester transfer protein TaqIB highly elevatesthe risk of coronary artery disease and type 2 diabetes mellitusrdquoHuman Genomics vol 6 article 20 2012
[84] A Assali M Ghayour-Mobarhan A Sahebkar et al ldquoAssoci-ation of angiotensin II type 1 receptor gene A1166C polymor-phismwith the presence of diabetesmellitus andmetabolic syn-drome in patients with documented coronary artery diseaserdquoEuropean Journal of Internal Medicine vol 22 no 3 pp 254ndash261 2011
[85] S Emamgholipour A Hossein-nezhad S A Mohajerani MShirzad and B Larijani ldquoAssociation between promoter resistingene polymorphism and coronary artery disease in diabetic andnon diabetic patientsrdquo Iranian Journal of Diabetes and LipidDisorders vol 10 no 2 pp 221ndash228 2009
[86] S Fallah M Seifi and A Samadikuchaksaraei ldquoRisk of coro-nary artery stenosis in Iranian type 2 diabetics is there a rolefor matrix metalloproteinase-3 gene (-1612 5A6A) polymor-phismrdquo Journal of Physiology and Biochemistry vol 66 no 4pp 359ndash364 2010
[87] A Vaisi-Raygani Z Rahimi H Tavilani and T PourmotabbedldquoButyrylcholinesterase K variant and the APOE-epsilon 4 allelework in synergy to increase the risk of coronary artery diseaseespecially in diabetic patientsrdquo Molecular Biology Reports vol37 no 4 pp 2083ndash2091 2010
[88] Z Rahimi H Nomani H Mozafari et al ldquoFactor v G1691Aprothrombin G20210A and methylenetetrahydrofolate reduc-tase polymorphism C677T are not associated with coronaryartery disease and type 2 diabetes mellitus in western IranrdquoBlood Coagulation amp Fibrinolysis vol 20 no 4 pp 252ndash2562009
[89] M Nakhjavani F Esfahanian A Jahanshahi et al ldquoThe rela-tionship between the insertiondeletion polymorphism of theACE gene and hypertension in Iranian patients with type 2diabetesrdquoNephrology Dialysis Transplantation vol 22 no 9 pp2549ndash2553 2007
[90] A Vaisi-Raygani Z Rahimi H Nomani H Tavilani and TPourmotabbed ldquoThe presence of apolipoprotein 1205764 and 1205762alleles augments the risk of coronary artery disease in type 2diabetic patientsrdquoClinical Biochemistry vol 40 no 15 pp 1150ndash1156 2007
[91] Z Rahimi F Shahvaisi-Zadeh S Sadeghei M Vessal andN Yavari ldquoeNOS 4ab polymorphism and its interaction witheNOSG894T variants in type 2 diabetesmellitus modifying therisk of diabetic nephropathyrdquoDiseaseMarkers vol 34 no 6 pp437ndash443 2013
[92] Z Rahimi O Mansouri Zaveleh Z Rahimi and A AbbasildquoAT2R -1332 GA polymorphism and diabetic nephropathyin type 2 diabetes mellitus patientsrdquo Journal of Renal InjuryPrevention vol 2 no 3 pp 97ndash101 2013
[93] F Shahsavar A Kheirollahi M Jafarzadeh and M hedayatildquoSUMO4 M55V Polymorphism is associated with diabeticnephropathy in Iranian type 2 diabetes patientsrdquo Life ScienceJournal vol 10 no 5 pp 485ndash487 2013
[94] M K Arababadi M R Mirzaei S M A Sajadi et al ldquoInter-leukin (IL)-10 gene polymorphisms are associated with type 2diabeteswith andwithout nephropathy a study of patients fromthe Southeast Region of Iranrdquo Inflammation vol 35 no 3 pp797ndash802 2012
[95] A Nikzamir A Esteghamati A A Hammedian and T Mah-moudi ldquoThe role of vascular endothelial growth factor +405GC polymorphism and albuminuria in patients with type 2diabetes mellitusrdquo Molecular Biology Reports vol 39 no 2 pp881ndash886 2012
[96] Z Rahimi A Hasanvand and V Felehgari ldquoInteraction ofMTHFR 1298C with ACE D allele augments the risk of diabeticnephropathy inWestern IranrdquoDNAand Cell Biology vol 31 no4 pp 553ndash559 2012
[97] Z Rahimi A Vaisi-Raygani and A Parsian ldquoConcomitantpresence of endothelial nitric oxide 894T and angiotensinII-converting enzyme D alleles are associated with diabeticnephropathy in a Kurdish population from Western IranrdquoNephrology (Carlton Vic) vol 17 no 2 pp 175ndash181 2012
[98] V Felehgari Z Rahimi H Mozafari and A Vaisi-RayganildquoACE gene polymorphism and serum ACE activity in Iranianstype II diabetic patients with macroalbuminuriardquo Molecularand Cellular Biochemistry vol 346 no 1-2 pp 23ndash30 2011
[99] Y Jafari Z Rahimi A Vaisi-Raygani and M Rezaei ldquoInter-action of eNOS polymorphism with MTHFR variants increasethe risk of diabetic nephropathy and its progression in type 2diabetesmellitus patientsrdquoMolecular and Cellular Biochemistryvol 353 no 1-2 pp 23ndash34 2011
[100] Z Rahimi V Felehgari M Rahimi et al ldquoThe frequency offactor V Leiden mutation ACE gene polymorphism serumACE activity and response to ACE inhibitor and angiotensin IIreceptor antagonist drugs in Iranians type II diabetic patientswith microalbuminuriardquoMolecular Biology Reports vol 38 no3 pp 2117ndash2123 2011
[101] M K Arababadi ldquoInterleukin-4 gene polymorphisms in type 2diabetic patients with nephropathyrdquo Iranian Journal of KidneyDiseases vol 4 no 4 pp 302ndash306 2010
[102] R Nosratabadi M K Arababadi V A Salehabad et al ldquoPoly-morphisms within exon 9 but not intron 8 of the vitamin Dreceptor are associated with the nephropathic complication oftype-2 diabetesrdquo International Journal of Immunogenetics vol37 no 6 pp 493ndash497 2010
[103] M Rahimi A Hasanvand Z Rahimi et al ldquoSynergistic effectsof the MTHFR C677T and A1298C polymorphisms on theincreased risk of micro- and macro-albuminuria and pro-gression of diabetic nephropathy among Iranians with type 2diabetes mellitusrdquo Clinical Biochemistry vol 43 no 16-17 pp1333ndash1339 2010
[104] A Nikzamir A Esteghamati M Feghhi M Nakhjavani ARashidi and J Z Reza ldquoThe insertiondeletion polymorphismof the angiotensin-converting enzyme gene is associated withprogression but not development of albuminuria in Iranianpatients with type 2 diabetesrdquo Journal of the Renin-Angiotensin-Aldosterone System vol 10 no 2 pp 109ndash114 2009
[105] A RNikzamir T GolmohammadiMNakhjavaniM Zahraeiand A A Amirzargar ldquoAngiotensin converting enzyme genepolymorphism in Iranian patients with type 2 diabetesrdquo IranianJournal of Immunology vol 3 no 1 pp 23ndash29 2006
[106] N Abbasi Z Salehi and Y Alizadeh ldquoAnalysis of glutathioneS-transferase M1 (GSTM1) deletion in diabetic retinopathyrdquoJournal of Guilan University of Medical Sciences vol 88 pp 34ndash40 2013
[107] A Dadbinpour M Sheikhha M Darbouy and M Afkhami-Ardekani ldquoInvestigating GSTT1 and GSTM1 null genotype asthe risk factor of diabetes type 2 retinopathyrdquo Journal of Diabetesamp Metabolic Disorders vol 12 no 1 pp 48ndash53 2013
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Journal of Diabetes Research 21
[108] M Feghhi A Nikzamir A Esteghamati T Mahmoudi andM S Yekaninejad ldquoRelationship of vascular endothelial growthfactor (VEGF) +405GC polymorphism and proliferativeretinopathy in patients with type 2 diabetesrdquo TranslationalResearch vol 158 no 2 pp 85ndash91 2011
[109] M M Amoli S Hasani-Ranjbar N Roohipour et al ldquoVEGFgene polymorphism association with diabetic foot ulcerrdquo Dia-betes Research and Clinical Practice vol 93 no 2 pp 215ndash2192011
[110] H Chu MWang D Zhong et al ldquoAdipoQ polymorphisms areassociated with type 2 diabetes mellitus a meta-analysis studyrdquoDiabetesMetabolism Research and Reviews vol 29 no 7 pp532ndash545 2013
[111] J Wang J Zhang L Li et al ldquoAssociation of rs12255372 in theTCF7L2 gene with type 2 diabetes mellitus a meta-analysisrdquoBrazilian Journal of Medical and Biological Research vol 46 no4 pp 382ndash393 2013
[112] M Saadat ldquoNull genotypes of glutathione S-transferase M1(GSTM1) and T1 (GSTT1) polymorphisms increased suscepti-bility to type 2 diabetesmellitus ameta-analysisrdquoGene vol 532no 1 pp 160ndash162 2013
[113] S-T Tang C-J Wang H-Q Tang Q Zhang and Y WangldquoEvaluation of glutathione S-transferase genetic variants affect-ing type 2 diabetes susceptibility a meta-analysisrdquo Gene vol530 no 2 pp 301ndash308 2013
[114] J-H Zhong A C Rodrıguez N-N Yang and L-Q Li ldquoMeth-ylenetetrahydrofolate reductase gene polymorphism and risk oftype 2 diabetes mellitusrdquo PLoS ONE vol 8 no 9 Article IDe74521 2013
[115] S Yang J Zhang C Feng and G Huang ldquoMTHFR 677 Tvariant contributes to diabetic nephropathy risk in Caucasianindividuals with type 2 diabetes a meta-analysisrdquo MetabolismClinical and Experimental vol 62 no 4 pp 586ndash594 2013
[116] Y Hua J Shen Y Song Y Xing and X Ye ldquoInterleukin-10minus2592CAminus2819CT andminus21082AG polymorphismswith riskof type 2 diabetes mellitus a HuGE review and meta-analysisrdquoPLoS ONE vol 8 no 6 Article ID e66568 2013
[117] MA-HHelaly E-S ZHatataMAbu-Elmagd et al ldquoAssocia-tion of IL-10 and IL-6 gene polymorphisms with type 2 diabetesmellitus among Egyptian patientsrdquo European Journal of GeneralMedicine vol 10 no 3 pp 158ndash162 2013
[118] S Vats V Sambyal andA J S Bhanwer ldquoGenetic links betweencoronary artery disease and type 2 diabetesrdquo Human BiologyReview vol 2 no 2 pp 90ndash119 2013
[119] G Wang Q Zhang N Xu et al ldquoAssociations between twopolymorphisms (FokI and BsmI) of vitamin D receptor geneand type 1 diabetes mellitus in Asian population a meta-analysisrdquo PLoS ONE vol 9 no 3 Article ID e89325 2014
[120] K TizaouiWKaabachi AHamzaoui andKHamzaoui ldquoCon-tribution of VDR polymorphisms to type 1 diabetes suscep-tibility systematic review of case-control studies and meta-analysisrdquo Journal of Steroid Biochemistry andMolecular Biologyvol 143 pp 240ndash249 2014
[121] L Sun Q Yuan N Cao et al ldquoVEGF genetic polymorphismsmay contribute to the risk of diabetic nephropathy in patientswith diabetes mellitus a meta-analysisrdquo The Scientific WorldJournal vol 2014 Article ID 624573 11 pages 2014
[122] B S Dellamea L C F Pinto C B Leitao K G Santos and LH S Canani ldquoEndothelial nitric oxide synthase gene polymor-phisms and risk of diabetic nephropathy a systematic reviewand meta-analysisrdquo BMC Medical Genetics vol 15 article 92014
[123] Z J Ma R Chen H-Z Ren X Guo J G Chen and L-M Chen ldquoEndothelial nitric oxide synthase (eNOS) 4bapolymorphism and the risk of diabetic nephropathy in type 2diabetes mellitus a meta-analysisrdquoMeta Gene vol 2 no 1 pp50ndash62 2014
[124] MG EhmMCKarnoubH Sakul et al ldquoGenomewide searchfor type 2 diabetes susceptibility genes in four american popu-lationrdquoThe American Journal of Human Genetics vol 66 no 6pp 1871ndash1881 2000
[125] F Busfield D L Duffy J B Kesting et al ldquoA genomewidesearch for type 2 diabetes-susceptibility genes in indigenousAustraliansrdquo American Journal of Human Genetics vol 70 no2 pp 349ndash357 2002
[126] S C Elbein M D Hoffman K Teng M F Leppert and S JHasstedt ldquoA genome-wide search for type 2 diabetes suscep-tibility genes in Utah Caucasiansrdquo Diabetes vol 48 no 5 pp1175ndash1182 1999
[127] C N Rotimi G Chen A A Adeyemo et al ldquoA genome-widesearch for type 2 diabetes susceptibility genes inWest AfricansrdquoDiabetes vol 53 no 3 pp 838ndash841 2004
[128] S Cauchi D Meyre E Durand et al ldquoPost genome-wide asso-ciation studies of novel genes associated with type 2 diabetesshow gene-gene interaction and high predictive valuerdquo PLoSONE vol 3 no 5 Article ID e2031 2008
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
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