Toll-like receptor 3 and geographic atrophy in age-related macular degeneration

被引：165

作者：

Yang, Zhenglin ^{[1
,3
,4
,5
]}

Stratton, Charity ^{[5
]}

Francis, Peter J. ^{[6
]}

Kleinman, Mark E. ^{[7
]}

Tan, Perciliz L. ^{[2
]}

Gibbs, Daniel ^{[5
]}

Tong, Zongzhong ^{[5
]}

Chen, Haoyu ^{[1
,5
]}

Constantine, Ryan ^{[5
]}

Yang, Xian ^{[1
,5
]}

Chen, Yuhong ^{[1
,5
]}

Zeng, Jiexi ^{[1
,5
]}

Davey, Lisa ^{[2
]}

Ma, Xiang ^{[5
]}

Hau, Vincent S. ^{[5
]}

Wang, Chi ^{[2
]}

Harmon, Jennifer ^{[5
]}

Buehler, Jeanette ^{[5
]}

Pearson, Erik ^{[5
]}

Patel, Shrena ^{[5
]}

Kaminoh, Yuuki ^{[5
]}

Watkins, Scott ^{[5
]}

Luo, Ling ^{[5
]}

Zabriskie, Norman A. ^{[5
]}

Bernstein, Paul S. ^{[5
]}

Cho, Wongil ^{[7
]}

Schwager, Andrea ^{[5
]}

Hinton, David R. ^{[9
]}

Klein, Michael L. ^{[6
]}

Hamon, Sara C. ^{[10
]}

Simmons, Emily ^{[6
]}

Yu, Beifeng ^{[5
]}

Campochiaro, Betsy ^{[2
]}

Sunness, Janet S. ^{[2
,8
]}

Campochiaro, Peter ^{[2
]}

Jorde, Lynn ^{[5
]}

Parmigiani, Giovanni ^{[2
]}

Zack, Donald J. ^{[2
]}

Katsanis, Nicholas ^{[2
]}

Ambati, Jayakrishna ^{[7
]}

Zhang, Kang ^{[1
,5
,11
]}

机构：

[1] Univ Calif San Diego, Shiley Eye Ctr, San Diego, CA 92037 USA

[2] Johns Hopkins Univ, Inst Med Genet, Baltimore, MD 21205 USA

[3] Sichuan Acad Med Sci, Chengdu, Peoples R China

[4] Sichuan Prov Peoples Hosp, Chengdu, Peoples R China

[5] Univ Utah, Sch Med, Salt Lake City, UT USA

[6] Oregon Hlth & Sci Univ, Portland, OR 97201 USA

[7] Univ Kentucky, Lexington, KY USA

[8] Greater Baltimore Med Ctr, Baltimore, MD USA

[9] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA

[10] Rockefeller Univ, New York, NY 10021 USA

[11] Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2008年 / 359卷 / 14期

基金：

美国国家卫生研究院;

关键词：

D O I：

10.1056/NEJMoa0802437

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND Age- related macular degeneration is the most common cause of irreversible visual impairment in the developed world. Advanced age- related macular degeneration consists of geographic atrophy and choroidal neovascularization. The specific genetic variants that predispose patients to geographic atrophy are largely unknown. METHODS We tested for an association between the functional toll- like receptor 3 gene ( TLR3) variant rs3775291 ( involving the substitution of phenylalanine for leucine at amino acid 412) and age- related macular degeneration in Americans of European descent. We also tested for the effect of TLR3 Leu and Phe variants on the viability of human retinal pigment epithelial cells in vitro and on apoptosis of retinal pigment epithelial cells from wild- type mice and Tlr3- knockout ( Tlr3(-/-)) mice. RESULTS The Phe variant ( encoded by the T allele at rs3775291) was associated with protection against geographic atrophy ( P = 0.005). This association was replicated in two independent case - control series of geographic atrophy ( P = 5.43 x 10(-4) and P = 0.002). No association was found between TLR3 variants and choroidal neovascularization. A prototypic TLR3 ligand induced apoptosis in a greater fraction of human retinal pigment epithelial cells with the Leu - Leu genotype than those with the Leu - Phe genotype and in a greater fraction of wild- type mice than Tlr3(-/-) mice. CONCLUSIONS The TLR3 412Phe variant confers protection against geographic atrophy, probably by suppressing the death of retinal pigment epithelial cells. Since double- stranded RNA ( dsRNA) can activate TLR3- mediated apoptosis, our results suggest a role of viral dsRNA in the development of geographic atrophy and point to the potential toxic effects of short- interfering- RNA therapies in the eye.

引用

页码：1456 / U57

页数：19

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