HDL cholesterol esters mediate the genetic link between sedentary behavior and urological cancers: Insights from mediation and validation analyses

This study explores the causal relationship between sedentary behavior and urological cancers, focusing on bladder cancer (BC), prostate cancer, and kidney cancer, using Bayesian Mendelian randomization and mediation analysis. A two-sample Mendelian randomization (MR) framework was employed, using genetic variants as instrumental variables. Bayesian and multivariate MR assessed causal effects of sedentary behaviors (TV watching, computer use, driving) on urological cancers. Sensitivity analyses (MR-Egger, MR-PRESSO, and Cochran Q) ensured robustness. Mediation analysis identified high-density lipoprotein (HDL) cholesterol ester levels as a primary mediator, validated through meta-analysis. Prolonged TV watching was significantly associated with increased BC risk (OR = 2.908; 95% CI = 1.221-6.930; P = .015). Mediation analysis showed small HDL cholesterol ester levels mediated 17.5% of this effect. No causal relationships were observed between computer use or driving and the cancers. Sensitivity analyses confirmed robust findings without heterogeneity or pleiotropy. Prolonged TV watching increases BC risk, mediated by small HDL cholesterol ester levels. Sedentary behavior is a modifiable risk factor, highlighting the importance of lifestyle interventions in prevention.