The CFH–CFHR5 Locus in Wet Age-Related Macular Degeneration, Polypoidal Choroidal Vasculopathy, and Central Serous Chorioretinopathy

AbstractPurpose To evaluate the effects of haplotype-tagging single-nucleotide polymorphisms (SNPs) in the CFH–CFHR5 locus on neovascular age-related macular degeneration (nAMD), polypoidal choroidal vasculopathy (PCV) and chronic central serous chorioretinopathy (cCSCR) in Chinese. Design Case-control genetic association study. Participants A total of 846 patients (341 nAMD, 288 PCV, and 217 cCSCR including 43 with secondary macular neovascularization MNV) and 632 healthy Chinese controls. Methods A total of 17 candidate SNPs were initially selected from the CFH–CFHR5 region; after excluding five SNPs that deviated from Hardy–Weinberg equilibrium, 12 SNPs were retained for the final analysis. Association analyses included logistic regression adjusted for age and sex, and haplotype-based analysis using Haploview. Study-wide significance threshold was set at PPMain Outcome Measures Associations between individual SNPs and haplotypes in the CFH–CFHR5 locus with nAMD, PCV, and cCSCR (with or without MNV), respectively. Results The tagging SNP, rs12144939, for the CFHR3/1 deletion was significantly associated with nAMD (OR=0.37, P=0.0031). Notably, we identified three candidate variants showing novel associations with PCV, including rs12144939 (OR=0.29, P=6.29×10-4), rs423641 in CFHR1 (OR=0.74, 95% CI: 0.60 – 0.91, P=0.0038), and rs10922152 in CFHR5 (OR=1.55, P=0.0031). No SNP in this locus was associated with cCSCR without MNV, whereas CFH rs529825 was nominally associated with cCSCR with MNV (OR=0.47, P=0.0047). Similar patterns of haplotype associations were observed across the three maculopathies. Notably, the haplotype A-T-C-G spanning CFHR4, CFHR2 and CFHR5 (OR=1.81, permutation P=0.0099) and haplotype G-A-G within CFHR5 (OR=1.56, permutation P=0.025) were specifically associated with PCV. Conclusions This study validates the association of the CFHR3/1 deletion (tagged by rs12144939) with nAMD. Furthermore, we reveal a novel genetic architecture for PCV within the CFH–CFHR5 locus, characterized by associations at rs12144939, rs423641 (CFHR1), and rs10922152 (CFHR5), as well as risk haplotypes unique to PCV. These findings underscore the critical role of CFH-related genes in PCV and provide new insights into its genetic mechanisms.