A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration.
Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world and has a strong genetic predisposition. A locus at human chromosome 10q26 affects the risk of AMD, but the precise gene(s) have not been identified. We genotyped 581 AMD cases and 309 normal controls in a Caucasian cohort in Utah. We demonstrate that a single-nucleotide polymorphism, rs11200638, in the promoter region of HTRA1 is the most likely causal variant for AMD at 10q26 and is estimated to confer a population attributable risk of 49.3%. The HTRA1 gene encodes a secreted serine protease. Preliminary analysis of lymphocytes and retinal pigment epithelium from four AMD patients revealed that the risk allele was associated with elevated expression levels of HTRA1 mRNA and protein. We also found that drusen in the eyes of AMD patients were strongly immunolabeled with HTRA1 antibody. Together, these findings support a key role for HTRA1 in AMD susceptibility and identify a potential new pathway for AMD pathogenesis.
Yang
Zhenglin
Z
Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Camp
Nicola J
NJ
Sun
Hui
H
Tong
Zongzhong
Z
Gibbs
Daniel
D
Cameron
D Joshua
DJ
Chen
Haoyu
H
Zhao
Yu
Y
Pearson
Erik
E
Li
Xi
X
Chien
Jeremy
J
Dewan
Andrew
A
Harmon
Jennifer
J
Bernstein
Paul S
PS
Shridhar
Viji
V
Zabriskie
Norman A
NA
Hoh
Josephine
J
Howes
Kimberly
K
Zhang
Kang
K
D000368:Aged; D000375:Aging; D000483:Alleles; D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006720:Homozygote; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010857:Pigment Epithelium of Eye / Q000201:enzymology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015593:Retinal Drusen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics
D012333:RNA, Messenger; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases