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

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 PatelYuuki Kaminoh, Scott Watkins, Ling Luo, Norman A. Zabriskie, Paul S. Bernstein, Wongil Cho, Andrea Schwager, David R. Hinton, Michael 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

Research output: Contribution to journalArticle

166 Citations (Scopus)

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 = 5.43 × 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.

Original languageEnglish (US)
Pages (from-to)1456-1463
Number of pages8
JournalNew England Journal of Medicine
Volume359
Issue number14
DOIs
StatePublished - Oct 2 2008

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Geographic Atrophy
Toll-Like Receptor 3
Macular Degeneration
Retinal Pigments
Epithelial Cells
Genes
Choroidal Neovascularization
Double-Stranded RNA
Apoptosis
Knockout Mice
leucyl-phenylalanine
leucylleucine
Genotype
Poisons
Vision Disorders
Viral RNA
Phenylalanine
Leucine
Small Interfering RNA
Alleles

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Yang, Z., Stratton, C., Francis, P. J., Kleinman, M. E., Tan, P. L., Gibbs, D., ... Zhang, K. (2008). Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. New England Journal of Medicine, 359(14), 1456-1463. https://doi.org/10.1056/NEJMoa0802437

Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. / Yang, Zhenglin; Stratton, Charity; Francis, Peter J.; Kleinman, Mark E.; Tan, Perciliz L.; Gibbs, Daniel; Tong, Zongzhong; Chen, Haoyu; Constantine, Ryan; Yang, Xian; Chen, Yuhong; Zeng, Jiexi; Davey, Lisa; Ma, Xiang; Hau, Vincent S.; Wang, Chi; Harmon, Jennifer; Buehler, Jeanette; Pearson, Erik; Patel, Shrena; Kaminoh, Yuuki; Watkins, Scott; Luo, Ling; Zabriskie, Norman A.; Bernstein, Paul S.; Cho, Wongil; Schwager, Andrea; Hinton, David R.; Klein, Michael; Hamon, Sara C.; Simmons, Emily; Yu, Beifeng; Campochiaro, Betsy; Sunness, Janet S.; Campochiaro, Peter; Jorde, Lynn; Parmigiani, Giovanni; Zack, Donald J.; Katsanis, Nicholas; Ambati, Jayakrishna; Zhang, Kang.

In: New England Journal of Medicine, Vol. 359, No. 14, 02.10.2008, p. 1456-1463.

Research output: Contribution to journalArticle

Yang, Z, Stratton, C, Francis, PJ, Kleinman, ME, Tan, PL, Gibbs, D, Tong, Z, Chen, H, Constantine, R, Yang, X, Chen, Y, Zeng, J, Davey, L, Ma, X, Hau, VS, Wang, C, Harmon, J, Buehler, J, Pearson, E, Patel, S, Kaminoh, Y, Watkins, S, Luo, L, Zabriskie, NA, Bernstein, PS, Cho, W, Schwager, A, Hinton, DR, Klein, M, Hamon, SC, Simmons, E, Yu, B, Campochiaro, B, Sunness, JS, Campochiaro, P, Jorde, L, Parmigiani, G, Zack, DJ, Katsanis, N, Ambati, J & Zhang, K 2008, 'Toll-like receptor 3 and geographic atrophy in age-related macular degeneration', New England Journal of Medicine, vol. 359, no. 14, pp. 1456-1463. https://doi.org/10.1056/NEJMoa0802437
Yang Z, Stratton C, Francis PJ, Kleinman ME, Tan PL, Gibbs D et al. Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. New England Journal of Medicine. 2008 Oct 2;359(14):1456-1463. https://doi.org/10.1056/NEJMoa0802437
Yang, Zhenglin ; Stratton, Charity ; Francis, Peter J. ; Kleinman, Mark E. ; Tan, Perciliz L. ; Gibbs, Daniel ; Tong, Zongzhong ; Chen, Haoyu ; Constantine, Ryan ; Yang, Xian ; Chen, Yuhong ; Zeng, Jiexi ; Davey, Lisa ; Ma, Xiang ; Hau, Vincent S. ; Wang, Chi ; Harmon, Jennifer ; Buehler, Jeanette ; Pearson, Erik ; Patel, Shrena ; Kaminoh, Yuuki ; Watkins, Scott ; Luo, Ling ; Zabriskie, Norman A. ; Bernstein, Paul S. ; Cho, Wongil ; Schwager, Andrea ; Hinton, David R. ; Klein, Michael ; Hamon, Sara C. ; Simmons, Emily ; Yu, Beifeng ; Campochiaro, Betsy ; Sunness, Janet S. ; Campochiaro, Peter ; Jorde, Lynn ; Parmigiani, Giovanni ; Zack, Donald J. ; Katsanis, Nicholas ; Ambati, Jayakrishna ; Zhang, Kang. / Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. In: New England Journal of Medicine. 2008 ; Vol. 359, No. 14. pp. 1456-1463.
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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 = 5.43 × 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.",
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AU - Yang, Zhenglin

AU - Stratton, Charity

AU - Francis, Peter J.

AU - Kleinman, Mark E.

AU - Tan, Perciliz L.

AU - Gibbs, Daniel

AU - Tong, Zongzhong

AU - Chen, Haoyu

AU - Constantine, Ryan

AU - Yang, Xian

AU - Chen, Yuhong

AU - Zeng, Jiexi

AU - Davey, Lisa

AU - Ma, Xiang

AU - Hau, Vincent S.

AU - Wang, Chi

AU - Harmon, Jennifer

AU - Buehler, Jeanette

AU - Pearson, Erik

AU - Patel, Shrena

AU - Kaminoh, Yuuki

AU - Watkins, Scott

AU - Luo, Ling

AU - Zabriskie, Norman A.

AU - Bernstein, Paul S.

AU - Cho, Wongil

AU - Schwager, Andrea

AU - Hinton, David R.

AU - Klein, Michael

AU - Hamon, Sara C.

AU - Simmons, Emily

AU - Yu, Beifeng

AU - Campochiaro, Betsy

AU - Sunness, Janet S.

AU - Campochiaro, Peter

AU - Jorde, Lynn

AU - Parmigiani, Giovanni

AU - Zack, Donald J.

AU - Katsanis, Nicholas

AU - Ambati, Jayakrishna

AU - Zhang, Kang

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N2 - 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 × 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.

AB - 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 × 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.

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