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AMD Genetic Pathogenesis

AMD Genetic Pathogenesis. Peng ZHOU, M.D . Age-related Macular Degeneration (AMD). 50%. Abobe 50 years old. 45%. Aging population increasing Elderly population over 143 million Will reach 200 million by 2014. 40%. 35%. 30%. 25%. 20%. 15%. 10%. 5%. 0%. 2010. 2030. 2050. 1950.

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AMD Genetic Pathogenesis

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  1. AMD Genetic Pathogenesis Peng ZHOU, M.D.

  2. Age-related Macular Degeneration (AMD) 50% Abobe 50 years old 45% • Aging population increasing • Elderly population over 143 million • Will reach 200 million by 2014 40% 35% 30% 25% 20% 15% 10% 5% 0% 2010 2030 2050 1950 1970 1990 23.5 25% 20.2 • Prevalence of AMD increased with age • About 20% in Shanghai over 70 y/o • 25% in the United States over 70 y/o 20% Prevalence of AMD 13.5 15% 10% 5.7 5% 0% 80岁- 50岁- 60岁- 70岁- 上图：Population division of the dept of the United Nations Secretariat, world population prospects,2004 下图：邹海东,等.中华眼科杂志.2005;41:15-19Klein R, et.al Am J Ophthalmol.2004; 137:486-495 2

  3. Age-related Macular Degeneration (AMD) No. 1 cause of blindness in U.S. No. 1 irreversible blindness developed world Congdon N.Arch Ophthalmol. 2004:122:477-85. Klein R, et.al Am J Ophthalmol.2004; 137:486-495 • Becoming No. 1 cause of blindness inChina • 7.6-15.5% in China over the age of 50 • 21.4 million AMD patients in China 黄晓波,等.中华眼科杂志.2009;45:786-92 3

  4. Pathogenesis of AMD Environment (smoking) Immune Neovascularization Oxidative stress Genetics Previous research: Fragmented 1. No complete theory for AMD pathogenesis 2. Can not explain the different phenotypes

  5. AMD pathogenesis hypothesis The sequence of different mechanisms : Immunology Genetics Oxidative Stress Neovascularization Scar

  6. AMD pathogenesis of the research strategy 遗传与环境 • Previous Strategy has its limitations • Population genetics provides an effective way • Theoretically, in a large population, the disease-causing gene polymorphism will lead to changes of AMD susceptibility • Our research strategy: ： Exon sequencing  AMD susceptibility genes Gene function  the pathogenesis of AMD

  7. 一、Exon sequencing 遗传与环境 • Exon sequencing found many new genes • Needs more samples • HERPUD1 and COL15A1 related to PCV • An important way for early screening of PCV

  8. 二、 Functional Studies of Four genes 遗传与环境 • ARMS2 • CFH • HTRA1 • TLR3

  9. 1、ARMS2 ◆ Background: • ARMS2 is associated with AMD ◆ In our study： • Associated with AMD in Chinese Population • New CNV associated SNPs • New PCV associated SNPs • Difference between CNV and PCV 遗传与环境 Cheng Y, Li XX, et.al. Genetic and Functional Dissection of ARMS2 in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy. PloS ONE

  10. 1、ARMS2 遗传与环境 ◆ Background: • The mechanism of ARMS2 in unclear ◆ In our study： • ARMS2 mutation plasmid affect the biological behavior of the vascular endothelial cells and RPE cell proliferation, adhesion and migration M 对照野生型突变型 55k Da 43k Da 34k Da 增殖能力：突变型＞野生型＞对照组，有统计学差异 ARMS2野生型、突变型基因蛋白表达升高

  11. 2、CFH ◆ Background: • CFH is associated with AMD ◆ In our study： • Associated with AMD in Chinese Population • Published in 2012 IOVS 遗传与环境 Tian J, Li XX. et.al Association of Genetic Polymorphisms and Age-Related Macular Degeneration in Chinese Population. Invest Ophthalmol Vis Sci. 2012;53:4262–4269

  12. 2、CFH ◆ Background: • The mechanism of CFH in unclear ◆ In our study： • H402Y significantly increases binding capacity of CFH to oxidizing lipids • Link genetic - oxidative stress - immune - neovascularization together • Support our proposal • PNAS in press 遗传与环境 CFH genotypes impact risk of AMD by interaction with oxidized phospholipids PNAS 2012

  13. 3、HTRA1 ◆ Background: • HTRA1 is associated with AMD ◆ In our study： • Associated with AMD in Chinese Population • New CNV associated SNPs • New PCV associated SNPs • Difference between CNV and PCV 遗传与环境 Jiang JJ, Li XX, et.al. Overexpression of HTRA1 Leads to Down-regulation of Fibronectin and Functional Changes in RF/6A Cells and HUVECs. PloS ONE

  14. 3、HTRA1 ◆ Background: • HTRA1is a serine protease • The mechanism of HTRA1 in unclear ◆ In our study： • Destruct the vessel wall, lead to PCV like lesions • Published in 2011 PNAS 遗传与环境 Jones A, Zhang K, et.al. Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice. PNAS 2011:108:14578–14583

  15. 3、HTRA1 ◆ Furthermore： • HTRA1through Differentiation Factor 6 lead to CNV • Published in 2011 JBC 遗传与环境 Zhang L, Zhang K, et.al. High Temperature Requirement Factor A1 (HTRA1) Gene Regulates Angiogenesis through Transforming Growth Factor- Family Member Growth Differentiation Factor 6. JBC. 2012: 287:1520–1526

  16. 4、TLR3 ◆ Background: • TLR3 is NOT associated with wet AMD ◆ In our study： • TLR3Exon sequencing • Associated with wet AMD in Chinese Population 遗传与环境 Sun YY, Li XX, et.al. Role of TLR3 C1234T Variant on Choroidal Neovascularization is Controversial between Meta Analysis and Experimental Study. IOVS

  17. 4、TLR3 遗传与环境 ◆ Background: • The mechanism of TLR3 in GA in unclear ◆ In our study： • TLR3 rs5743391decreases the binding capacity of TLR3 to dsRNA • Protects against from GA

  18. Molecular Pathogenesis of AMD Multi-gene diseases Each gene mutation may lead to AMD Genetic - environment interactions lead to different phenotypes Four genes play an important role in the pathogenesis of AMD Genetics Oxidation CFH HTRA1 Immunology GDF6 Elastase TRL3 Neovascularization PCV ARMS2 CNV Upstream needs further investigation Geographic Atrophy Scar

  19. Thanks！

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