Association of CFH rs1061170 (Y402H), C2 rs9332739 (E318D), and C3 rs2230199 (R102G) gene polymorphism with age-related macular degeneration: an integrative systematic review, meta-analysis, and in-silico approach

BACKGROUND: Age-related macular degeneration (AMD) is a progressive retinal disorder and a major cause of irreversible blindness in the elderly, with complement pathway dysfunction playing a key role in its pathogenesis. METHODS: The present aims to examine the impact of CFH rs1061170 (Y402H), C2 rs9332739 (E318D), and C3 rs2230199 (R102G) gene polymorphisms and AMD risk, in addition, Deleterious missense SNPs in CFH, C2, and C3 were analyzed for stability, conservation, and structural impact using multiple computational approaches. Relevant studies were searched in PubMed, Web of Science, and Google Scholar databases between the years Jan 2020 and 30 April 2026 and covered a total of nine case-control articles. Functional prediction analyses using SIFT, PolyPhen-2, I-Mutant, ConSurf, and Project HOPE suggested that the missense variants in CFH, C2, and C3 may alter protein structure, stability, and intermolecular interactions, providing biological support for their potential role in AMD pathogenesis. ConSurf showed that the SNPs were located in functional residues. Project HOPE revealed alterations in amino acid size, charge, and hydrophobicity, which may impair intermolecular interactions and destabilize protein architecture. CONCLUSION: The present meta-analysis demonstrated significant associations of CFH rs1061170 (Y402H) and C3 rs2230199 (R102G) polymorphisms with AMD susceptibility, whereas C2 rs9332739 (E318D) showed a nonsignificant trend toward reduced AMD susceptibility. In-silico analyses suggested that these variants may influence complement protein function through localized alterations in electrostatic properties, ligand-binding interactions, and surface physicochemical characteristics rather than major global structural destabilization. These computational findings provide plausible mechanistic insights into complement-mediated retinal dysfunction but require experimental validation before establishing molecular causality.