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de Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD
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De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

Dec 23, 2015

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Page 1: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

de Jong P. N Engl J Med 2006;355:1474-1485

Selected Candidate Genes Most Likely Associated with AMD

Page 2: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.
Page 3: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.
Page 4: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

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%

Page 5: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.
Page 6: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

Seddon JM et al. Arch Ophthalmol. 2006 Jul;124(7):995-1001.

Page 7: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.
Page 8: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.
Page 9: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

Science 261, 821

Page 10: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

Science 261, 821

Page 11: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

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

Page 12: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

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.

Page 13: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

N Engl J Med. 2008 Oct 23;359(17):1811-21.

Page 14: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

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

Page 15: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

Endotheliale Stickstoff Synthase (NOS3)

5'

+1

T>C pos-786

ATG

Translation

Promoter 3'

Glu>Asp Codon 298

Exon 7Promoter Intron 4

Ins>Del

Page 16: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.
Page 17: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.
Page 18: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

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

Page 19: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

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.

Page 20: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

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

Page 21: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

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

Page 22: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

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

Page 23: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

The Lancet 2001;357(9255):505-508.

Page 24: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.
Page 25: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

N Engl J Med. 2008 Mar 6;358(10):999-1008.

Page 26: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

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%

Page 27: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.
Page 28: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

Kohnke H et al. Eur J Clin Pharmacol. 2005 Jul;61(5-6):381-8. Epub 2005 Jun 11.

Page 29: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

N Engl J Med. 2008 Jan 10;358(2):169-76.

Page 30: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.
Page 31: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

Nature. 2008 Feb 21;451(7181):929-36.

Page 32: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

Roden DM, N Engl J Med. 2008 Jan 10;358(2):169-76.

Page 33: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

Roden DM, N Engl J Med. 2008 Jan 10;358(2):169-76.

Page 34: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

Roden DM, N Engl J Med. 2008 Jan 10;358(2):169-76.

Page 35: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

N Engl J Med 2008;359(8):789-799.

Page 36: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

Circulation 2004; 110(19):3136-3142.

Page 37: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

N Engl J Med. 2008 Jun 26;358(26):2796-803.

Page 38: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

Foulkes WD, N Engl J Med. 2008 Nov 13;359(20):2143-53.

Breast-Cancer Susceptibility Loci and Genes

Page 39: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

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

Page 40: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

Pharoah PD et al. N Engl J Med. 2008 Jun 26;358(26):2796-803.

Established Common Breast-Cancer Susceptibility Alleles

Page 41: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

N Engl J Med. 2008 Feb 28;358(9):910-9. Epub 2008 Jan 16.

Page 42: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.
Page 43: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

Kanasaki K et al. Nature. 2008 Jun 19;453(7198):1117-21. Epub 2008 May 11.

Schematic illustration of 2-ME synthesis by COMT

Page 44: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

Präeklampsie

Plazentare Östrogene ↓

2-Methroxyöstradiol ↓

Hypoxie inducible Factor 1

Trophoblastinvasion in Spiralarterien

Page 45: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

supprimiert

Hypoxia inducible Factor 1 (HIF12)

suluble Fms like Tyrosin Kinase 1(= löslicher VEGF Receptor)

2 Methoxyöstradiol

Page 46: De Jong P. N Engl J Med 2006;355:1474-1485 Selected Candidate Genes Most Likely Associated with AMD.

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

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