Causal Association of Adipose Tissue with Bladder Cancer and the Mediating Effects of Circulating Metabolites: A Mendelian Randomization Study

<b>Background:</b> Previous studies have indicated that there is an association between obesity and bladder cancer (BCa). However, the relationship between fat distribution, which is more representative of the risk of obesity, and BCa remains unclear. This study aimed to investigate the causal relationship between fat distribution and BCa, and the mediating role of circulating metabolites. <b>Methods:</b> The necessary data were obtained from a large Genome-Wide Association Studies (GWAS) database. Two-sample and two-step Mendelian randomization (MR) analyses were performed to investigate the association between fat distribution and BCa, as well as the mediating effect of circulating metabolites. The inverse variance weighted (IVW) method was the main analysis method. Heterogeneity tests, horizontal pleiotropy analyses, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) tests, and leave-one-out analyses were performed to assess the stability of the results. <b>Results:</b> The IVW method indicated that abdominal subcutaneous adipose tissue adjusted for body mass index (BMI) and height (ASATadj) and abdominal subcutaneous/gluteofemoral adipose tissue (ASAT/GFAT) increased the risk of BCa. The odds ratio (OR) for ASATadj was 1.78 (95% CI=1.27-2.50, p=0.001) and that for ASAT/GFAT was 1.64 (95% CI=1.01-2.66, p=0.047). Furthermore, two-step MR analysis revealed that the effect of ASAT/GFAT on BCa was mediated by valine (proportion mediated: 7.13%, 95% CI = 3.57%-10.69%, p=0.045). <b>Conclusions:</b> Our research shows that, unlike most studies which focus on visceral fat, ASAT also impacts human health by increasing the risk of BCa, with the blood metabolite valine involved in this process. Monitoring and reducing ASAT accumulation can help reducce the disease burden of BCa.