Abstract:AIM: To investigate the causal effect of obesity on cataract risk and explores the potential mediating roles of metabolites using Mendelian randomization (MR). METHODS: Summary-level data from large-scale genome-wide association studies to examine the relationship between obesity and cataract were utilized. Obesity-related traits, including body mass index (BMI), waist-to-hip ratio (WHR), and waist circumference (WC). A two-sample MR approach was employed to assess the causal effect of obesity on cataract risk, while potential mediators were identified from suitable genome-wide association studies (GWAS) datasets. Additionally, a metabolic pathway analysis was conducted. RESULTS: An increase of 1 standard deviation (SD) in BMI, WHR, and WC was associated with a significantly higher risk of cataract (BMI: odds ratio (OR) 1.0017, 95% confidence interval (CI): 1.0001–1.0032, P=0.0320; WHR: OR 1.0029, 95%CI: 1.0006–1.0051, P=0.0129; WC: OR 1.0020, 95%CI: 1.0001–1.0038, P=0.0390]. These associations remained robust after adjusting for confounding factors in multivariable MR analysis. Furthermore, a two-step MR analysis identified eight potential metabolic mediators, with one mediator showing a significant causal role in the relationship between obesity and cataract. CONCLUSION: This work highlights the importance of addressing obesity as a modifiable risk factor for cataracts, particularly through metabolic pathways.
