title: Toll-like receptor 3 and geographic atrophy in age-related macular degeneration.
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.
authors.affiliation: Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Yang
authors.forename: Charity
authors.initials: C
authors.lastname: Stratton
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Francis
authors.forename: Mark E
authors.initials: ME
authors.lastname: Kleinman
authors.forename: Perciliz L
authors.initials: PL
authors.lastname: Tan
authors.forename: Daniel
authors.initials: D
authors.lastname: Gibbs
authors.forename: Zongzhong
authors.initials: Z
authors.lastname: Tong
authors.forename: Haoyu
authors.initials: H
authors.lastname: Chen
authors.forename: Ryan
authors.initials: R
authors.lastname: Constantine
authors.forename: Xian
authors.initials: X
authors.lastname: Yang
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Chen
authors.forename: Jiexi
authors.initials: J
authors.lastname: Zeng
authors.forename: Lisa
authors.initials: L
authors.lastname: Davey
authors.forename: Xiang
authors.initials: X
authors.lastname: Ma
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Hau
authors.forename: Chi
authors.initials: C
authors.lastname: Wang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Harmon
authors.forename: Jeanette
authors.initials: J
authors.lastname: Buehler
authors.forename: Erik
authors.initials: E
authors.lastname: Pearson
authors.forename: Shrena
authors.initials: S
authors.lastname: Patel
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Kaminoh
authors.forename: Scott
authors.initials: S
authors.lastname: Watkins
authors.forename: Ling
authors.initials: L
authors.lastname: Luo
authors.forename: Norman A
authors.initials: NA
authors.lastname: Zabriskie
authors.forename: Paul S
authors.initials: PS
authors.lastname: Bernstein
authors.forename: Wongil
authors.initials: W
authors.lastname: Cho
authors.forename: Andrea
authors.initials: A
authors.lastname: Schwager
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.forename: Michael L
authors.initials: ML
authors.lastname: Klein
authors.forename: Sara C
authors.initials: SC
authors.lastname: Hamon
authors.forename: Emily
authors.initials: E
authors.lastname: Simmons
authors.forename: Beifeng
authors.initials: B
authors.lastname: Yu
authors.forename: Betsy
authors.initials: B
authors.lastname: Campochiaro
authors.forename: Janet S
authors.initials: JS
authors.lastname: Sunness
authors.forename: Peter
authors.initials: P
authors.lastname: Campochiaro
authors.forename: Lynn
authors.initials: L
authors.lastname: Jorde
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Zack
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Jayakrishna
authors.initials: J
authors.lastname: Ambati
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang