Modifiable Dietary Habits, Inflammatory Mediation, and Senile Cataract: Unraveling Causality via Mendelian...

Senile cataract (SC) is a major cause of global vision impairment and blindness, posing a significant public health challenge in aging populations. This study employed Mendelian randomization (MR) using genetic instruments for 83 dietary habits from the UK Biobank GWAS, with SC data from the FinnGen R12 as the outcome. We employed multiple MR methods, including bidirectional MR, replication sample MR, and multivariable MR (MVMR), to identify dietary habits significantly associated with SC. The potential mediating effects of inflammatory biomarkers were further assessed using a two-step MR. Finally, to validate the core findings, additional analyses employed independent datasets for the overall cataract phenotype and the cataract surgical endpoint. After false discovery rate correction and validation in an independent cohort, meal-aligned alcohol consumption, compared to drinking apart from meals, demonstrated a substantial and robust protective causal effect against SC (OR = 0.67; 95% CI = 0.55-0.82; p = 5.86 × 10^-5). MVMR sustained this independent protective effect after adjusting for 15 outcome-related confounders. Mediation analysis indicated partial mediation through inflammatory pathways, with IL-6 accounting for 11% and CRP for 6% of the effect. Further analyses using independent datasets also linked this drinking pattern to a reduced likelihood of undergoing cataract surgery (OR = 0.99; 95% CI = 0.98-0.99; p = 2.34 × 10^-6) and a lower risk of overall cataract (OR = 0.83; 95% CI = 0.76-0.91; p = 5.26 × 10^-5). This study reveals that, compared to drinking without meals, consuming alcohol with meals causally reduces SC risk among current drinkers, partially mediated through inflammatory pathways. These findings suggest that alcohol-related nutritional strategies for SC should therefore shift focus from solely type and quantity to include consumption timing.