Toll-like Receptor 3 and Geographic Atrophy in Age-Related Macular Degeneration
Open accessAbstract
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.
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More recently, an association between AMD and Toll-like receptor 3 was reported, but this association was not replicated in other large cohorts.
“More recently, an association between AMD and another Toll-like receptor 3 (TLR3) was reported (168), but this association was not replicated in other large cohorts (41).”
From Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration (2009) · cites this paper as [168]
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“The L412F variant of the TLR3 gene (i.e. a leucine to phenylalanine change at amino acid 412), encoded by the T allele at rs3775291 of the TLR3 gene, has been reported in three case-control cohorts to be protective against dry AMD, possibly through suppression of RPE apoptosis (Yang et al., 2008).”
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- Authors
- Yang, Z., Stratton, C., Francis, P. J., Kleinman, M. E., Tan, P. L., Gibbs, D., Tong, Z., Chen, H., Constantine, R., Yang, X., Chen, Y., Zeng, J., Davey, L., Ma, X., Hau, V. S., Wang, C., Harmon, J., Buehler, J., Pearson, E., Patel, S., Kaminoh, Y., Watkins, S., Luo, L., Zabriskie, N. A., Bernstein, P. S., Cho, W., Schwager, A., Hinton, D. R., Klein, M. L., Hamon, S. C., Simmons, E., Yu, B., Campochiaro, B., Sunness, J. S., Campochiaro, P., Jorde, L., Parmigiani, G., Zack, D. J., Katsanis, N., Ambati, J., & Zhang, K.
- Affiliations
- University of Utah (US)
- Oregon Health & Science University (US)
- University of Kentucky (US)
- Johns Hopkins University (US)
- University of Southern California (US)
- Rockefeller University (US)
- Greater Baltimore Medical Center (US)
- Peking University (CN)
- ORCID
- Yang, Zhenglin
- Francis, Peter J.
- Kleinman, Mark E.
- Tan, Perciliz L.
- Gibbs, Daniel
- Chen, Haoyu
- Yang, Xian
- Chen, Yuhong
- Wang, Chi
- Harmon, Jennifer
- Pearson, Erik
- Luo, Ling
- Bernstein, Paul S.
- Hinton, David R.
- Hamon, Sara C.
- Sunness, Janet S.
- Campochiaro, Peter
- Jorde, Lynn
- Parmigiani, Giovanni
- Zack, Donald J.
- Katsanis, Nicholas
- Ambati, Jayakrishna
- Zhang, Kang
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2008-10-02
- Volume
- 359
- Issue
- 14
- Pages
- 1456-1463
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC2573951
- OpenAlex
- W2113975222
- Cited by
- 222
- References
- 41
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 4 · 2021: 12 · 2020: 7 · 2019: 4 · 2018: 6 · 2017: 8 · 2016: 8 · 2015: 14 · 2014: 17 · 2013: 18 · 2012: 29
- FWCI
- 26.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Massachusetts Medical Society
- National Eye Institute (R01EY014448, R01EY014428)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- TLR3, geographic atrophy, age-related macular degeneration, retinal pigment epithelial cells, apoptosis, choroidal neovascularization, double-stranded RNA, genetic association
- MeSH terms
- Animals, Genotype, Humans, Interferon Inducers, Macula Lutea, Macular Degeneration, Pigment Epithelium of Eye, Poly I-C, RNA, Double-Stranded, RNA, Viral, Case-Control Studies, Apoptosis, Mice, Knockout, Choroidal Neovascularization, Polymorphism, Single Nucleotide, RNA, Small Interfering, Toll-Like Receptor 3, Mice, In Vitro Techniques
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