title: A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration.
abstract: 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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Yang
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Camp
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.forename: Zongzhong
authors.initials: Z
authors.lastname: Tong
authors.forename: Daniel
authors.initials: D
authors.lastname: Gibbs
authors.forename: D Joshua
authors.initials: DJ
authors.lastname: Cameron
authors.forename: Haoyu
authors.initials: H
authors.lastname: Chen
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhao
authors.forename: Erik
authors.initials: E
authors.lastname: Pearson
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chien
authors.forename: Andrew
authors.initials: A
authors.lastname: Dewan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Harmon
authors.forename: Paul S
authors.initials: PS
authors.lastname: Bernstein
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
authors.forename: Norman A
authors.initials: NA
authors.lastname: Zabriskie
authors.forename: Josephine
authors.initials: J
authors.lastname: Hoh
authors.forename: Kimberly
authors.initials: K
authors.lastname: Howes
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
mesh_terms: 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
chemical_list: D012333:RNA, Messenger; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases