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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. - PowerPoint PPT Presentation
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AMD Genetic PathogenesisPeng ZHOU, M.D.
Aging population increasingElderly population over 143 million Will reach 200 million by 2014
0%5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
1950 1970 1990 2010 2030 2050
Abo
be 5
0 ye
ars
old
0%
5%
10%
15%
20%
25%
50岁 - 60岁 - 70岁 - 80岁 -Prev
alen
ce o
f AM
D
5.7
13.5
20.2
23.5
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
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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
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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)
Oxidativ
e stress
Neovascularization
Immune
Genetics
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 SNPsNew PCV associated SNPsDifference 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 !