Work

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

Year: 2025

Type: article

Abstract: Purpose 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 P <0.0042 for allelic tests (Bonferroni-corrected for 12 SNPs) and at P <0.05 for haplotype tests (adjusted using 10,000 permutations). Main 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.

Source: Ophthalmology Science

DOI: 10.1016/j.xops.2025.101043