de Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD
Dec 23, 2015
Age-Related Eye Disease Study Research Group. Arch Ophthalmol 2001;119:1417-36.
Vitamin C
Vitamin E
-Carotin
Zinkoxid
Kupferoxid
500 mg
400 mg
15 mg
80 mg
2 mg
Erkrankungsreduktion in 5 Jahren um 25%
Drug class potential mechanism
Cholesterol Anti- Anti- Aß
homoeostasis inflammatory angiogenetic effects
ACE inhibitors - + - ?
All blockers - + - ?
PPARG agonists - + - ?
ACAT inhibitors + ? - ?
Statins + + + +
Aspirin - + + -
NSAIDs - + + +
COX2 inhibitors - + + ?
Thienopyridines- ? ? ?
+ indicates positive; - indicates negative
0,01 0,1 1 10
Risk of Incident AD: The Effect of HT
Men
Women: No HT Use
Past HT Use <3 Years
Past HT Use 3-10 Years
Past HT Use >10 Years
Current HT Use <3 years
Current HT Use 3-10 Years
Current HT Use >10 Years
Relative Hazard (95% CI)
Mean Age, 74 Years
Zandi PP, et al. JAMA. 2002;288:2123-9.
Khosla UM et al. Kidney Int 2005;67:1739-42.
Mazzali M et al. Am J Physiol Renal Physiol 2002;282:F991-F997.
Sánchez-Lozada LG et al. Am J Physiol Renal Physiol 2007;292:F1238-F1244.
Hyperurikämie
Renale Vasokonstriktion
Reduktion des Stickmonoxyds
Erhöhung des RAS
Endotheliale Stickstoff Synthase (NOS3)
5'
+1
T>C pos-786
ATG
Translation
Promoter 3'
Glu>Asp Codon 298
Exon 7Promoter Intron 4
Ins>Del
polymorphic 287 bp insertion/deletion sequence
5‘ 3‘
INTRON 16 of the ACE gene
Angiotensin I-Converting Enzym (ACE)
Polymorphism: Ins/Del (287bp) in Intron 16
Rigat B et al. J Clin Invest. 1990 Oct;86(4):1343-6.
Serum immunoreactive ACE concentrations (ag/liter) forindividual with the II, ID, and DD genotypes, respectively,
shown in left, middle, and right panels.
Nakagawa T et al. Am J Physiol Renal Physiol 2006;290:F625-F631.
Sánchez-Lozada LG et al. Am J Physiol Renal Physiol 2008;294:F710-F718.
Fructose:
entleert ATP
erhöht Harnsäure
erhöht Risiko des metabolischen Syndroms
Choi JW et al. Arthritis Rheum 2008;59:109-16.
Ueno M et al. J Hypertens Suppl 1988;6:S50-S51.
Metabolisches Syndrom
Reduktion der Fruktose
Reduktion purinreicher Kost
Reduktion der Harnsäure
Reduktion von Bleikontamination
Chang FM et al. Biol Res Pregnancy Perinatol 1987:8:35-9.
Feig DI et al. Kidney Int 2004;66:281-7.
HarnsäuretransferMutter-Fetus
Harnsäure wirkt angiostatisch
Harnsäure reduziert fetale Nephrone
WARFARIN BENÖTIGTE INDIVIDUALDOSIS
KALIBIRIERT AN CYP 2C9 *1• CYP 2 C 9
• 1*/2* 80 %• 2*/2* 20 %• 1*/3* 56 %• 2*/2* 23 %• 3*/3* 9%
Mammakarzinom
RR > 5,0 Breast-cancer gene 1, Breast-cancer gene 2 Tumor protein p53Phosphatase and tensin homologueSerine-threonine protein kinase 11E-cadherin
(<0.5)(<0,5)(<0,1)(<0,1)
RR 1,5 – 5,0 Cell-cycle–checkpoint kinaseAtaxia–telangiectasia mutatedPartner and localizer of BRCA2BRCA1-interacting protein C-terminal helicase 1
RR 1,01 – 1,5 Caspase 8Fibroblast growth factor receptor 2 (ER pos)Mitogen-activated protein kinase kinase kinase 1Tox high-mobility group box family member 3 (ER pos)Lymphocyte-specific protein 1
Pharoah PD et al. N Engl J Med. 2008 Jun 26;358(26):2796-803.
Established Common Breast-Cancer Susceptibility Alleles
Kanasaki K et al. Nature. 2008 Jun 19;453(7198):1117-21. Epub 2008 May 11.
Schematic illustration of 2-ME synthesis by COMT
Präeklampsie
Plazentare Östrogene ↓
2-Methroxyöstradiol ↓
Hypoxie inducible Factor 1
Trophoblastinvasion in Spiralarterien
supprimiert
Hypoxia inducible Factor 1 (HIF12)
suluble Fms like Tyrosin Kinase 1(= löslicher VEGF Receptor)
2 Methoxyöstradiol
Kanasaki K et al. Nature. 2008 Jun 19;453(7198):1117-21. Epub 2008 May 11.
A hypothetical working model of preeclampsia derived from our studies with COMT/2-ME
Supplementary Figure 15