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