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Previous Volume 359:1456-1463 October 2, 2008 Number 14 Next

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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.

Source Information

From the Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China (Z.Y.); University of Utah School of Medicine, Salt Lake City (Z.Y., C.S., D.G., Z.T., H.C., R.C., X.Y., Y.C., J.Z., X.M., V.S.H., J.H., J.B., E.P., S.P., Y.K., S.W., L.L., N.A.Z., P.S.B., A.S., B.Y., L.J., K.Z.); Oregon Health & Science University, Portland (P.J.F., M.L.K., E.S.); University of Kentucky, Lexington (M.E.K., W.C., J.A.); Johns Hopkins University (P.L.T., L.D., C.W., B.C., J.S.S., P.C., G.P., D.J.Z., N.K.) and Greater Baltimore Medical Center (J.S.S.) — both in Baltimore; University of California San Diego, San Diego (Z.Y., H.C., X.Y., Y.C., J.Z., K.Z.); Keck School of Medicine of the University of Southern California, Los Angeles (D.R.H.); Rockefeller University, New York (S.C.H.), and Institute of Molecular Medicine, Peking University, Beijing, China (K.Z.).

Dr. Z. Yang, Ms. Stratton, and Drs. Francis and Kleinman contributed equally to this article.

This article (10.1056/NEJMoa0802437) was published at www.nejm.org on August 27, 2008.

Address reprint requests to Dr. Zhang at Shiley Eye Center, University of California at San Diego, San Diego, CA 92037, or at kangzhang{at}ucsd.edu; or to Dr. Katsanis at the Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, or at nkatsan1{at}jhmi.edu.

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