Health Disparities in Common, Complex Diseases: a Role for Genetics? Prof. Kathleen C. Barnes The screen versions of these slides have full details of copyright and acknowledgements 1 1 Health Disparities in Common, Complex Diseases: a Role for Genetics? Kathleen C. Barnes, PhD Associate Professor of Medicine Mary Beryl Patch Turnbull Scholar Director, Johns Hopkins Bayview Genetic Research Facility and Genomics Core 2 Overview Common, complex diseases are characterized by health disparities, not limited to socioeconomic disparities, but including race and ethnicity Is there a genetic basis for these disparities (i.e., asthma) If yes, what is the evolutionary basis for selection of variants that confer risk to a common disease? Is the basis for this selection rooted in adaptations in the innate and adaptive immune response? 3 Communicable diseases, maternal and perinatal conditions, and nutritional deficiencies 30% Injuries 9% Other chronic diseases 9% Diabetes 2% Chronic respiratory diseases 7% Cancer 13% Cardiovascular diseases 30% 60% www.who.int/chp Chronic diseases Reality: 80% of chronic disease deaths occur in low and middle income countries Cardiovascular disease, mainly heart disease, stroke Cancer Chronic respiratory diseases Diabetes
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Health Disparities in Common, Complex Diseases:
a Role for Genetics?
Prof. Kathleen C. Barnes
The screen versions of these slides have full details of copyright and acknowledgements 1
1
Health Disparities in Common, Complex Diseases: a Role for Genetics?
Kathleen C. Barnes, PhD
Associate Professor of Medicine
Mary Beryl Patch Turnbull Scholar
Director, Johns Hopkins Bayview
Genetic Research Facility and Genomics Core
2
Overview
� Common, complex diseases are characterized by health disparities, not limited to socioeconomic disparities, but including race and ethnicity
� Is there a genetic basis for these disparities (i.e. , asthma)
� If yes, what is the evolutionary basis for selection of variants that confer risk to a common disease?
� Is the basis for this selection rooted in adaptationsin the innate and adaptive immune response?
3
Communicable diseases, maternal
and perinatal
conditions, and nutritional
deficiencies
30%
Injuries9%
Other chronic diseases9%
Diabetes2%
Chronic respiratory
diseases
7%
Cancer13%
Cardiovascular diseases
30%
60%
www.who.int/chp
Chronic diseasesReality: 80% of chronic disease deaths occur
in low and middle income countries
� Cardiovascular disease,
mainly heart disease, stroke
� Cancer
� Chronic respiratory diseases
� Diabetes
Health Disparities in Common, Complex Diseases:
a Role for Genetics?
Prof. Kathleen C. Barnes
The screen versions of these slides have full details of copyright and acknowledgements 2
4
The worldwide prevalence of asthma
Asher, MI, et al. , Eur. Resp. J., 1998, 12: 315-335
5
Disease African American European American
HTN (45-64 yrs) 344.7
(per 1,000)
207.8
(per 1,000)
CHD (death) 140.4
(per 100,000)
102.1
(per 100,000)
Diabetes (45-64yrs) 121.4
(per 1,000)
55.8
(per 1,000)
Asthma (children) 8.9% 5.2%
The prevalence of common diseases is higher among African Americans
6
The impact of ethnicity on disease severity
CDC, 2000
Health Disparities in Common, Complex Diseases:
a Role for Genetics?
Prof. Kathleen C. Barnes
The screen versions of these slides have full details of copyright and acknowledgements 3
7Nature Genetics Supplement, November 2004
8
“Are genetic differences between populations likely to have a role in health status…?”
� Causes of health disparities likely derive from differences in:
� Social marginalization
� Environmental exposures
� Socioeconomic status
� Access to health care
� Education
� Diet
� Culture
� Discrimination
Francis S. Collins, 2004, Nature Genetics, 36 (11): S13-S15
9
Definition of complex traits
� Genetically heterogeneous
� Many distinct genes, or groups of genes, lead to similar clinical phenotypes
Health Disparities in Common, Complex Diseases:
a Role for Genetics?
Prof. Kathleen C. Barnes
The screen versions of these slides have full details of copyright and acknowledgements 4
10
CFTR geneMutation
Cystic fibrosis
Monogenic disease
Complex disease
Asthma
EthnicityAge SES
Environmentalfactor 1
Environmentalfactor 2
Gene 2 Gene 3
Gene 1 Gene 4
Adapted from Whittaker, PA, Current Opinion in Chemical Biology, 2001, 5: 352-359
11
Concordance for atopic disease in twins
P-values
Pairwise concordance
MZ DZAuthors
NS0.200.36Hopp, et al., 1984
NS0.350.50Bonini, et al., 1983
<0.050.200.56Wuthrich, et al., 1981
<0.010.160.25Edfors-Lubs, 1971
<0.010.350.86Charpin and Arnoud, 1971
<0.010.250.78Milani and Comparetti, 1970
NS0.440.55Parrot and Saindelle, 1962
NS0.490.61Gedda and Teodori, 1962
<0.010.090.50Harvald and Hauge, 1956
<0.050.630.88Spaich and Ostertage, 1936
12
118 genes total
25 ‘solid’ genes
Num
ber
of
gene
s
Number of study samples with positive associations
60
50
40
30
20
10
1 2-5 6-10 >10
Genes associated with asthma/atopy phenotypes
Ober and Hoffjan, 2006, Genes and Immunity
1 study only; ( ) equals #studies replication failed
Genes by positional cloning
Allergic responsegenes
HLA associations
118 genes total
25 ‘solid’ genes
Host defense (innate immunity) genes
Health Disparities in Common, Complex Diseases:
a Role for Genetics?
Prof. Kathleen C. Barnes
The screen versions of these slides have full details of copyright and acknowledgements 5
13
Concordance for atopic disease in twins
P-values
Pairwise concordance
MZ DZAuthors
NS0.200.36Hopp, et al., 1984
NS0.350.50Bonini, et al., 1983
<0.050.200.56Wuthrich, et al., 1981
<0.010.160.25Edfors-Lubs, 1971
<0.010.350.86Charpin and Arnoud, 1971
<0.010.250.78Milani and Comparetti, 1970
NS0.440.55Parrot and Saindelle, 1962
NS0.490.61Gedda and Teodori, 1962
<0.010.090.50Harvald and Hauge, 1956
<0.050.630.88Spaich and Ostertage, 1936
14
Definition of complex traits
� Genetically heterogeneous
� Many distinct genes, or groups of genes, lead to similar clinical phenotypes
� Multifactorial
� Disease expression is influenced by interactions
between multiple major and minor genes, and is modulated by interacting non-genetic factors
(e.g. , degree of allergen exposure)
15
GeneticEnvironmental
H2
1.00.50 0.6 0.7 0.8 0.90.1 0.2 0.3 0.4
Asthma/hay fever
TotalIgE
BHRspIgE
(B. tropicalis)
FEV1
Relative influence on trait development
Adapted from Hartl, D. L., (2000), A Primer of Population Genetics, Sunderland, M. A., Sinauer Associates, Inc
Pitch Fingerprintridge count
Height
Weight
Blood pressure
Handedness
Fertility
Health Disparities in Common, Complex Diseases:
a Role for Genetics?
Prof. Kathleen C. Barnes
The screen versions of these slides have full details of copyright and acknowledgements 6
16
σσσσ2EC
4.23 (0.57)
0.25 (0.34)
1.36 (0.46)
2.98 (0.68)
Additive geneticCommon family environment
Common sibling environment
Non-familial environmental
34%
3%15%
48%
Components of total variance in specific serum IgE levels against HDM and timothy grass (RAST index)
Palmer, et al. , Am. J. Respir. Crit. Care Med . , 161 (6), 2000, 1836-43
Environment
Genes
σσσσ2CS
σσσσ2C
s2A
17
Type A
Type B
Type I
Type II
Genes
Environment
Phenotype 1
Phenotype 2
Phenotype 3
Phenotype 4
Phenotype 5
Phenotype 6
Phenotype 7
Phenotype 8
Phenotype 9
Phenotype 10
Phenotype 11
Phenotype 12
18
The association between Dermatophagoides mites
and the increasing prevalence of asthma in village communities within the Papua New Guinea highlands
“…Allergy to house dust mites appears to be a significant feature
in the disease pathogenesis, and it is likely that this is associated
with modifications to traditional lifestyles by the recent introduction of blankets and changes
in sleeping habits that promote a more fertile environment for growth
and multiplication of mites“
Health Disparities in Common, Complex Diseases:
a Role for Genetics?
Prof. Kathleen C. Barnes
The screen versions of these slides have full details of copyright and acknowledgements 7
19
20
Achoo!Must be the roaches!
21
Environment or ethnicity?
Lowest income quartile
Highest income quartile0
.1
.2
.3
.4
Ave
rage
wh
eal d
iam
eter
to P
. am
eric
ana
African American European American
†: p<0.0001, compared to European American
Skin test sensitization to American cockroach in adolescents with asthma, deriving from the highest and lowest income quartiles according to ethnicity (African American vs. European American)
41Barnes, K. C., 2006, JACI, Feb., 117 (2): 243-54, 255-6
42
Amino acid sequence alignments of different tropomyosins
� Bla g 7 and Per a 7 have 97% sequence identity
� Per a 7 has 80% identity and 88% similarity with Der p 10 and Der f 10
� Per a 7 has substantial homology to helminthic tropomyosins from S. mansoni (72%), S. japonicum (72%), Onchocerca volvulus (70%), Caenorhabditis elegans (71%), and Brugia pahangi (67%)
Barnes, et al. , unpublished data
Health Disparities in Common, Complex Diseases:
a Role for Genetics?
Prof. Kathleen C. Barnes
The screen versions of these slides have full details of copyright and acknowledgements 15
43Barnes, K. C., 2006, JACI, Feb., 117 (2): 243-54, 255-6
44
Frequency distributions of log [total IgE (ng/ml)] among Amish and Barbadian subjects
The screen versions of these slides have full details of copyright and acknowledgements 17
49The Genetic Association Database, K. G. Becker, K. C. Barnes, T. J. Bright and S. A. Wang, Nature Genetics, 36: 431-432, (2004)
Genetic association database (http://geneticassocationdb.nih.gov)
50
‘Common variants/multiple disease’ hypothesis
� Common alleles contributing to a given disease under a certain
combination of interacting genes and environment al conditions
may act in other genetic backgrounds influenced
by other environment al factors
Different, possibly related clinical outcomes
Adapted from Becker, K. G., Med. Hypotheses, 2004, 62 (2): 309-17
LPS
Cockroach,dust mites
MLCKCD14
FCER1B
ADAM33
MHC DRB1
Asthma
= Gene= Behavioral trait= Environmental factor
Trauma
PLAT
Sepsis-associated ALI
F3
51Receptor required for P. vivax (malaria) infection of erythroid cellsIn the absence of the Duffy receptor, protection
Diego Ag
P AgLewis Ag
P. vivaxmerozoite
Duffy binding protein
Duffy Ag
� Alleles that are effective against one pathogen might be ineffective against another pathogen or for some other function
Pathogens and host counter-adaptations: “antagonistic pleiotropy”
� Pleiotropy = genes with > 1 distinct phenotypic effect
K. C. Barnes
Health Disparities in Common, Complex Diseases:
a Role for Genetics?
Prof. Kathleen C. Barnes
The screen versions of these slides have full details of copyright and acknowledgements 18
52
Frequencies of Duffy positive genotype
Population FY-NULL*1
Africans
Nigeria 0%
C. Afr. Rep. 0%
Europeans
England 100%
African Americans
New York 21%
Baltimore 14%
Caribbean
Barbados 21%
Jamaica 7%
White Americans
Pittsburgh 98%
Detroit 99%
Parra, et al. , 1998; Nickel, et al. , 1999
53
Duffy antigen/receptor for chemokines (DARC)
� Functions as a regulatory ‘sink’ for chemokines
Could the lack of expression of DARC result in sustained levels
of chemokines and promote features of CC chemokine-mediat ed
allergic inflammation?K. C. Barnes
1
2 3
4
56
7
C
C
� Point mutation in the DARC promoter
(T-46C) selectively abolishes the DARC expression on erythrocytes ⇒“Duffy-negative” phenotype (Fy(a-/b-))
� Expressed by subsets of endothelial as well as erythroid cells
� Binds with high affinity to chemokines of both the CXC and CC classes, which promote
the formation of acute and chronic inflammatory infiltrates, respectively
54
CCCT
TT
CCCT
TT
CCCT
TT
Genotype
0.0450.028
0.429
2.001-2.201
0.790
Total IgE
0.0330.026
0.494
2.133-2.233
0.684
Asthma severity
0.0360.016
0.294
2.095-2.410
1.050
Asthma (yes/no)
FBAT P-valueZ-ScorePhenotype
Family-based association test (FBAT) for DARC CC genotype* and asthma-associated phenotypes
*Fy a-/b-; N = 129 African Caribbean families
Vergara, et al. , in preparation
Health Disparities in Common, Complex Diseases:
a Role for Genetics?
Prof. Kathleen C. Barnes
The screen versions of these slides have full details of copyright and acknowledgements 19
55
Summary
� Common (chronic) diseases are complex traits resulting from a mix of major and minor effect genes and a host of environmental factors
� Genetic diversity for host susceptibility has resulted largely from pathogen/host counter-adaptations ⇒ a greater appreciation of these host responses may improve our understanding of disease pathology and prioritize candidate genes for complex diseases
� Consideration for genes that represent a shared genetic component between distinctly different clinical conditions: common variant/multiple disease hypotheses
� Differences in allelic frequencies in susceptibility genes could account for disparities observed between ethnic groups
56
Johns Hopkins Dept. of Medicine and SHPH
Audrey Grant Alkis Togias Terri BeatyWilliam Shao Roy Brower M. Danielle Fallin
Peter Chi Jon Sevransky Roxann Ashworth Peisong Gao Carl Shanholtz Alan F. Scott Li Gao Mark MossMonica Campbell Jim MaloneyEva Ehrlich Joe G. N. Garcia
Itael Evgey Mao YangMohan Parigi Maria Stockton
Kate HeldStacey Murray NHLBI ALI SCCOR faculty and staff
Acknowledgments
BarbadosPaul LevettHarold WatsonPissamai and Trevor Maul