title: HTRA1 variant confers similar risks to geographic atrophy and neovascular age-related macular degeneration.
abstract: Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy (GA) and choroidal neovascularization (wet AMD), represent two types of degenerative processes in the macula that lead to loss of central vision. Soft confluent drusen, characterized by deposits in macula without visual loss are considered a precursor of advanced AMD. A single nucleotide polymorphism, rs11200638, in the promoter of HTRA1 has been shown to increases the risk for wet AMD. However, its impact on soft confluent drusen and GA or the relationship between them is unclear. To better understand the role the HTRA1 polymorphism plays in AMD subtypes, we genotyped an expanded Utah population with 658 patients having advanced AMD or soft confluent drusen and 294 normal controls and found that the rs11200638 was significantly associated with GA. This association remains significant conditional on LOC387715 rs10490924. In addition, rs11200638 was significantly associated with soft confluent drusen, which are strongly immunolabeled with HTRA1 antibody in an AMD eye with GA similar to wet AMD. Two-locus analyses were performed for CFH Y402H variant at 1q31 and the HTRA1 polymorphism. Together CFH and HTRA1 risk variants increase the odds of having AMD by more than 40 times. These findings expand the role of HTRA1 in AMD. Understanding the underlying molecular mechanism will provide an important insight in pathogenesis of AMD.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: D Joshua
authors.initials: DJ
authors.lastname: Cameron
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Yang
authors.forename: Daniel
authors.initials: D
authors.lastname: Gibbs
authors.forename: Haoyu
authors.initials: H
authors.lastname: Chen
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Kaminoh
authors.forename: Adam
authors.initials: A
authors.lastname: Jorgensen
authors.forename: Jiexi
authors.initials: J
authors.lastname: Zeng
authors.forename: Ling
authors.initials: L
authors.lastname: Luo
authors.forename: Eric
authors.initials: E
authors.lastname: Brinton
authors.forename: Gregory
authors.initials: G
authors.lastname: Brinton
authors.forename: John M
authors.initials: JM
authors.lastname: Brand
authors.forename: Paul S
authors.initials: PS
authors.lastname: Bernstein
authors.forename: Norman A
authors.initials: NA
authors.lastname: Zabriskie
authors.forename: Shibo
authors.initials: S
authors.lastname: Tang
authors.forename: Ryan
authors.initials: R
authors.lastname: Constantine
authors.forename: Zongzhong
authors.initials: Z
authors.lastname: Tong
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
mesh_terms: D020256:Choroidal Neovascularization / Q000235:genetics*; D015331:Cohort Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D007150:Immunohistochemistry; D008268:Macular Degeneration / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases