Causal effects of antibody-mediated immunity to pathogens on five ophthalmic diseases: a Mendelian randomization study

While immune responses related to infections have been linked to ocular diseases, their causal role remains to be established. This study aimed to assess the causal relationship between antibody-mediated immune responses to infectious agents and five ocular conditions: chronic iridocyclitis (CIR), scleritis, wet age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma. We performed a two-sample Mendelian randomization (MR) analysis using GWAS data to assess causality between antibody responses to 46 pathogens and five ophthalmic diseases. The instrumental variables were Single nucleotide polymorphisms (SNPs). Causal estimates were primarily generated via the inverse-variance weighted method, supplemented by MR-Egger and weighted median methods. A Bonferroni-corrected threshold of P < 2.17 × 10^-4 was applied. Sensitivity analyses included Cochran's Q, MR-Egger, and MR-PRESSO for heterogeneity and pleiotropy. Reverse MR was performed to assess bidirectionality. Forward MR identified causal effects of infection-induced immune responses on ocular diseases. Epstein-Barr virus (EBV) ZEBRA antibodies were positively correlated with CIR, whereas Varicella zoster virus glycoproteins E and I antibodies were associated with scleritis and DR as risk factors. Genetically predicted anti-polyomavirus 2 IgG seropositivity (JCV IgG+) was identified as a risk factor for DR, wet AMD and glaucoma. In contrast, The EBV EBNA-1 antibody is associated with DR, wet AMD, and glaucoma as a protective factor, whereas the EBV VCA18 antibody is negatively associated with wet AMD. Reverse MR analysis indicated that DR may elevate JCV VP1 antibody levels. This study provides the first genetic evidence of a causal link between pathogen-specific immune responses and ocular diseases, offering a foundation for targeted immunomodulatory and personalized therapies.