A Mendelian Randomization Analysis of Obesity-Metabolite Pathways in Endometrial Cancer, Ovarian Cancer, Endometriosis, and Polycystic Ovary Syndrome

Abstract

Background:This study aimed to investigate the causal pathways that link obesity to the risk of gynecological diseases through specific circulating plasma metabolites. The diseases examined were endometrial cancer (EC), ovarian cancer (OC), endometriosis, and polycystic ovary syndrome (PCOS). A Mendelian randomization (MR) framework was used to identify and quantify the mediating role of metabolites.Methods:A three-stage, two-sample MR and mediation analysis was conducted. First, we estimated the causal effects of genetically predicted body mass index (BMI) and waist-hip ratio (WHR) on plasma metabolites. Second, we assessed the causal effects of the identified obesity-driven metabolites on four gynecological diseases. Finally, mediation analyses were performed to quantify the proportion of the obesity effect mediated by significant metabolites. Genetic instruments were derived from the largest available genome-wide association studies of European ancestry. The primary analytical method was inverse variance weighted (IVW), supplemented by sensitivity analyses.Results:Genetically predicted higher BMI showed evidence of causal effects for increased risks of EC, PCOS, and OC, whereas WHR showed no significant associations. BMI and WHR were associated with 218 and 172 plasma metabolites, respectively, with several metabolites identified as potential risk factors for gynecological diseases. For EC, these included androsterone sulfate and lipids within very low-density lipoprotein (VLDL), whereas for endometriosis, they included triglycerides within small VLDL and serum total triglycerides. Mediation analysis revealed that androsterone sulfate mediated 34.89% of the effect of BMI on EC risk, while serum total triglycerides mediated 22.41% of this effect.Conclusions:This study provides genetic evidence that general adiposity influences the risk of several gynecological diseases in part through specific metabolic pathways. Androgen and lipid metabolism emerged as candidate intermediate traits that explain a significant proportion of the effect of obesity on EC risk. These findings identify potential targets for risk stratification and preventive strategies.