Association Between LOC387715/HTRA1 and Japanese Exudative Age-Related Macular Degeneration

Abstract

Purpose: : Because there was no data available with regard to whether the single nucleotide polymorphism (SNP) in PLEKHA1/LOC387715/HTRA1 played the most important role in the development of Japanese exudative age-related macular degeneration (AMD) including polypoidal choroidal vasculopathy (PCV), we performed genotyping tagSNPs of HapMap based in addition to rs10490924 and rs11200638.

Methods: : Cases of 203 unrelated exudative AMD including PCV (mean age, 74.2 years; deviation, 8.05 years; male:female ratio, 72.5%:27.5%) were recruited at the Center for Macular Diseases, Department of Ophthalmology, Kyoto University Hospital, and at the Department of Ophthalmology, Fukushima Medical University Hospital. Based on the linkage disequilibrium (LD) block and the haplotype information for the Japanese and European populations that was provided by the HapMap project, we focused on the 85.2 kb DNA (from nucleotide number 124179187 to 124264414 in NT_030059.12), which encompassed PLEKHA1/LOC387715/HTRA1. For the genotyping study, additionally to previous reported risk allele of rs11200638 and rs10490924, we chose 25 additional tag SNPs from the rs10490924 and rs11200638 region that had minor allele frequencies greater than 0.2 and a square of the correlation coefficient r² >0.8 in the HapMap CEU or JPT (total 27 SNPs).

Results: : The HWE test indicated that all of the SNPs were at equilibrium in the control population. In the exudative macular disease population, however, rs10490924, rs3793917 and rs11200638 did not meet the HWE expectation. Linkage disequilibrium analysis demonstrated a strong LD (D' = 0.975) for rs10490924 G/T, rs3793917 G/C, and rs11200638 G/A and the formation of two exclusive haplotypes, G-G-G and T-C-A. When the haplotypes were inferred with a solid spine of D'>0.8, the LD, which included rs10490924 and rs11200638, was further extended to the 21 kb region between rs2736911 and rs2672587. Statistical analysis revealed that the statistical significance noted for the 7 out of the 10 SNPs that exhibited a potential association with AMD (P < 0.01) still remained even after correction for multiple testing .

Conclusions: : Strong LD containing rs10490924 and rs11200638 made indiscriminating which SNP is the most attributable for Japanese exudative AMD and PCV.

Keywords: age-related macular degeneration • genetics