HTRA1 variant confers similar risks to geographic atrophy and neovascular age-related macular degeneration.
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.
Cameron
D Joshua
DJ
Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Yang
Zhenglin
Z
Gibbs
Daniel
D
Chen
Haoyu
H
Kaminoh
Yuuki
Y
Jorgensen
Adam
A
Zeng
Jiexi
J
Luo
Ling
L
Brinton
Eric
E
Brinton
Gregory
G
Brand
John M
JM
Bernstein
Paul S
PS
Zabriskie
Norman A
NA
Tang
Shibo
S
Constantine
Ryan
R
Tong
Zongzhong
Z
Zhang
Kang
K
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
D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases