Toll-like Receptor 3 and Geographic Atrophy in Age-related Macular Degeneration

Overview

Journal N Engl J Med

Specialty General Medicine

Date 2008 Aug 30

PMID 18753640

Citations 106

Authors

Zhenglin Yang

Charity Stratton

Peter J Francis

Mark E Kleinman

Perciliz L Tan

Daniel Gibbs

Zongzhong Tong

Haoyu Chen

Ryan Constantine

Xian Yang

Yuhong Chen

Jiexi Zeng

Lisa Davey

Xiang Ma

Vincent S Hau

Chi Wang

Jennifer Harmon

Jeanette Buehler

Erik Pearson

Shrena Patel

Yuuki Kaminoh

Scott Watkins

Ling Luo

Norman A Zabriskie

Paul S Bernstein

Wongil Cho

Andrea Schwager

David R Hinton

Michael L Klein

Sara C Hamon

Emily Simmons

Beifeng Yu

Betsy Campochiaro

Janet S Sunness

Peter Campochiaro

Lynn Jorde

Giovanni Parmigiani

Donald J Zack

Nicholas Katsanis

Jayakrishna Ambati

Kang Zhang

Affiliations

Soon will be listed here.

Abstract

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=5.43x10(-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.

Citing Articles

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The contribution of pattern recognition receptor signalling in the development of age related macular degeneration: the role of toll-like-receptors and the NLRP3-inflammasome.

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