Genetic insights into metabolic traits and prostate cancer susceptibility: A two sample Mendelian Randomization study

Background : Metabolic syndrome (MetS) and its components have been implicated in prostate cancer, but observational associations remain inconsistent and vulnerable to confounding. We conducted a two-sample Mendelian randomization (MR) study to clarify whether major MetS traits causally influence prostate cancer risk. Methods : Genetic instruments for body mass index (BMI), waist circumference, systolic/diastolic blood pressure, fasting glucose, and lipid components such as triglycerides (TG), LDL-cholesterol, HDL-cholesterol, and total cholesterol were obtained from male-only large genome-wide association studies (UK Biobank) and MetS from multiple cohorts as exposure sets. Prostate cancer data set was derived from the FinnGen GWAS. Genome-wide significant variants (p<5×10⁻⁸) were clumped at r²<0.001. Causal estimates were calculated using inverse-variance weighted (IVW), weighted median, and MR-Egger methods. Heterogeneity (Cochran's Q), horizontal pleiotropy (MR-Egger intercept, MR-PRESSO), and sensitivity analyses were performed. Results : Higher genetically predicted fasting glucose was associated with reduced prostate cancer risk (OR 0.82, P=0.02). HDL-cholesterol (OR 1.52, P=0.052) and LDL-cholesterol (OR 0.87, P=0.07) showed suggestive effects. BMI, waist circumference, blood pressure, total cholesterol, and triglycerides showed no evidence of causal association. Conclusions : Our findings implicate glucose and lipid metabolism pathways in prostate cancer susceptibility. Given the exploratory nature and the predominantly European ancestry of the datasets, large scale studies including diverse multiple-ethnic populations are required to confirm these associations and clarify the role of metabolic traits across different ancestries in prostate cancer epidemiology.