AMD Genetic Pathogenesis

Peng ZHOU, M.D.

Aging population increasingElderly population over 143 million Will reach 200 million by 2014

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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;41:15-19 Klein R, et.al Am J Ophthalmol.2004; 137:486-495 2

Prevalence of AMD increased with age About 20% in Shanghai over 70 y/o 25% in the United States over 70 y/o

Age-related Macular Degeneration (AMD)

Becoming No. 1 cause of blindness in China

7.6-15.5% in China over the age of 50 21.4 million AMD patients in China

3

黄晓波 , 等 . 中华眼科杂志 .2009;45:786-92

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

Age-related Macular Degeneration (AMD)

Ox

idativ

e s

tres

s

Neovascularization

Immune

Ge

ne

tics

Environment (smoking)

Previous research: Fragmented1. No complete theory for AMD pathogenesis2. Can not explain the different phenotypes

Pathogenesis of AMD

AMD pathogenesis hypothesis

Genetics

Immunology

NeovascularizationOxidativeStress

Scar

The sequence of different mechanisms :

AMD pathogenesis of the research strategy

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

遗传与环境

一、 Exon sequencing Exon sequencing found many new genes

Needs more samples

HERPUD1 and COL15A1 related to PCV

An important way for early screening of PCV

遗传与环境

二、 Functional Studies of Four genes

ARMS2

CFH

HTRA1

TLR3

遗传与环境

1 、 ARMS2

遗传与环境

◆ 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

Cheng Y, Li XX, et.al. Genetic and Functional Dissection of ARMS2 in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy. PloS ONE

1 、 ARMS2 ◆ 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

遗传与环境

增殖能力：突变型＞野生型＞对照组，有统计学差异

M 对照 野生型 突变型

55k Da

43k Da

34k Da

ARMS2 野生型、突变型基因蛋白表达升高

2 、 CFH

遗传与环境

◆ Background:

CFH is associated with AMD

◆ In our study：Associated with AMD in Chinese Population

Published in 2012 IOVS

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

2 、 CFH

遗传与环境

◆ 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

CFH genotypes impact risk of AMD by interaction with oxidized phospholipids PNAS 2012

3 、 HTRA1

遗传与环境

◆ Background:

HTRA1 is associated with AMD

◆ In our study：Associated with AMD in Chinese Population New CNV associated SNPsNew PCV associated SNPsDifference between CNV and PCV

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

3 、 HTRA1

遗传与环境

◆ Background:HTRA1 is a serine protease

The mechanism of HTRA1 in unclear

◆ In our study：Destruct the vessel wall, lead to PCV like lesionsPublished in 2011 PNAS

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

3 、 HTRA1

遗传与环境

◆ Furthermore：

HTRA1through Differentiation Factor 6 lead to CNV

Published in 2011 JBC

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

4 、 TLR3

遗传与环境

◆ Background:

TLR3 is NOT associated with wet AMD

◆ In our study：

TLR3 Exon sequencing

Associated with wet AMD in Chinese Population

Sun YY, Li XX, et.al. Role of TLR3 C1234T Variant on Choroidal Neovascularization is Controversial between Meta Analysis and Experimental Study. IOVS

4 、 TLR3 ◆ 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

遗传与环境

Molecular Pathogenesis of AMD

Genetics

Multi-gene diseasesEach gene mutation may lead to AMD

Genetic - environment interactions lead to different phenotypesFour genes play an important role in the pathogenesis of AMD

HTRA1

Elastase

CFH

PCV

CNV

TRL3

GeographicAtrophy

ARMS2 Upstream needs further investigation

Oxidation

Immunology

Neovascularization

Scar

GDF6

Thanks ！