Mendelian randomization reveals that abnormal lipid metabolism mediates the causal relationship between body mass index and keratoconus

Abstract

Previous studies suggest that a high body mass index (BMI) may be a risk factor for keratoconus (KC), but the causal relationship remains unclear. This study used Mendelian randomization (MR) to investigate this connection and explore the mediating role of circulating serum metabolites and inflammatory factors in this association. Two-sample MR analysis was conducted to assess the relationship between BMI and KC. The study employed a two-step MR approach to evaluate the mediating roles of 91 inflammatory markers and 249 serum metabolites in the BMI-KC relationship. Inverse variance weighting (IVW) was the primary method, and multiple sensitivity analyses were performed to ensure robustness. IVW analysis revealed a positive causal relationship between BMI and KC (OR IVW = 1.811, 95% CI 1.005–3.262, P = 0.048). Although IL-12β and IL-4 were causally associated with KC, they did not mediate the BMI-KC relationship. Five serum metabolites were identified as potential mediators, with HDL cholesterol and triglyceride ratios showing significance. This study clarified the causal relationship between high BMI and KC, suggesting that high BMI may induce KC through lipid metabolism abnormalities. These findings underscore the importance of managing BMI for KC prevention.