Coding Variant I62V in the Complement Factor H Gene Is Strongly Associated with Polypoidal Choroidal Vasculopathy

Purpose: To investigate whether variants in the complement factor H (CFH) gene are associated with polypoidal choroidal vasculopathy (PCV). Design: Cross-sectional study. Participants: A case-control group of 130 PCV subjects and 173 unrelated controls. Methods: We conducted an association analysis between CFH variants and PCV in a Japanese population, genotyping 12 tag single nucleotide polymorphisms (SNPs)-including rs3753394, rs800292 (I62V), and rs1061170 (Y402H)-that are highly representative of the common genetic variation in the CFH region. Genotyping was performed using TaqMan technology. Main Outcome Measures: Allele and haplotype frequencies of the CFH variants. Results: A highly significant association with PCV was observed across the CFH region. The strongest association was observed at I62V (P = 1.7 x 10(-7)). Six other SNPs (rs3753394, rs6680396, rs1410996, rs2284664, rs1329428, and rs1065489) also showed significant association (10(-3) < p < 10(-6)). These associations became nonsignificant after accounting for rs800292 in a conditional logistic regression analysis. A significant omnibus haplotype association was detected in the entire CFH region (omnibus P = 1.6 x 10(-5) at 7 degrees of freedom). Conditional haplotype-based likelihood ratio tests revealed that the significant omnibus haplotype association disappeared when it was estimated conditional on I62V (omnibus P = 0.20, 6 degrees of freedom, post-I62V dependency), whereas the omnibus haplotype association remained significant when it was estimated conditional on any SNP other than I62V. These findings indicate that multiple observed effects were caused by linkage disequilibrium with I62V, and that this variant fully accounts for the association signals observed at the set of SNPs examined at this locus. Conclusions: The present study provides evidence that the complement pathway plays a substantial role in the pathogenesis of PCV. The nonsynonymous variant I62V is a plausible candidate for a causal polymorphism leading to the development of PCV, given its potential for functional consequences on the CFH protein and our own statistical evidence. Financial Disclosure(s): The authors have to proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2009;116:304-310 (C) 2009 by the American Academy of Ophthalmology.