Abstract / Summary
Abstract Background Prior studies on the relationship between body mass index (BMI) and age-related macular degeneration (AMD) have yielded inconsistent results. This may partly reflect BMI’s inability to distinguish fat from lean mass, which change with aging and may have divergent associations with AMD. Methods Survey-weighted cross-sectional National Health and Nutrition Examination Survey (NHANES) analyses examined BMI and relative fat mass (RFM) associations with AMD. Bidirectional two-sample Mendelian randomization (MR) evaluated BMI, appendicular lean mass (ALM), body fat percentage (BFP), and whole-body fat mass (BFM) across AMD phenotypes. Multivariable MR jointly modeled ALM and BFM; two-step MR evaluated 16 candidate inflammatory proteins. Benjamini–Hochberg false discovery rate (FDR) correction addressed multiple testing. Results Joint NHANES models suggested opposing associations of BMI and RFM with late AMD, with BMI inversely and RFM positively associated (both FDR-adjusted q = 0.128). In MR analyses, higher genetically predicted ALM was associated with lower odds of wet AMD (OR, 0.898; 95% CI, 0.807–0.998), whereas BFP (OR, 1.361; 95% CI, 1.080–1.714) and BFM (OR, 1.225; 95% CI, 1.042–1.439) were associated with higher odds (all phenotype-specific q < 0.05). MR provided no evidence of a BMI–AMD association. Multivariable MR provided nominal support for the ALM association after adjustment for BFM, while the BFM estimate was attenuated. Mediation analysis suggested that CX3CL1 may partly mediate the ALM–wet AMD association (estimated mediated proportion, 23.4%). Conclusions Lean and fat mass may have divergent associations with wet AMD, with CX3CL1 as a potential mediator. Prospective and experimental validation is needed.