Abstract
INTRODUCTION: The associations between excess adiposity and endometrial cancer (EC) risk may be mediated by altered metabolic profiles. Here, we triangulated evidence from observational and Mendelian randomisation (MR) analyses to investigate the relationship between adiposity traits, circulating metabolites, and their effects on endometrial cancer. METHODS: Observational analyses were performed in UK Biobank (N cases and controls = 1,005 and 215,339, respectively). Univariable and multivariable MR analyses were performed using female-specific summary statistics for adiposity traits (GIANT consortium; N BMI and WHR = 434,793 and 281,153, respectively), circulating metabolites (UK Biobank; N = 140,768) and EC (Endometrial Cancer Association Consortium; N cases and controls = 12,906 and 108,979, respectively). RESULTS: Higher body mass index (BMI) was associated with increased odds of overall EC, endometrioid EC, and non-endometrioid EC in both observational and MR analyses; however, there was weaker evidence for waist-hip-ratio (WHR). BMI was associated with 165 metabolites, 25 of which were associated with EC risk. Multivariable MR analyses suggest that several lipid metabolites and ratios may mediate the association between BMI and non-endometrioid EC, although analyses using Phenoscanner suggest that alternative pathways such as height and blood cell traits could influence the EC risk. CONCLUSION: Evidence here suggests that higher BMI causes a higher risk of overall and all histological subtypes of EC and variation in numerous circulating metabolites. Several of these metabolites showed relationships consistent with an intermediate role between BMI and non-endometrioid EC, however, further analyses highlighted other potential shared mechanisms that could influence the risk of EC.