Causal insights into immune cell profiles, plasma metabolites, and bladder cancer: A Mendelian randomization approach

This study aimed to investigate the causal associations between immune cells, plasma metabolites, and bladder cancer (BC) using Mendelian randomization (MR). Utilizing summary data from genome-wide association studies, the study examined the causal effects among 731 immune cell phenotypes, 1400 plasma metabolites, and BC. Bidirectional MR analysis was conducted to assess the links between immune cells and BC, and complemented by two-step mediation analysis and multivariate MR to identify potential mediating metabolites. Sixteen immune cell phenotypes were found to have causal associations with BC, including one with reverse causality. Additionally, 48 metabolites were identified as being causally associated with BC. Through two-step and multivariate MR analyses, 5 immune cell phenotypes and 5 plasma metabolites were identified as mediators in the causal pathway to BC. CD4+ activated cells was causally associated with BC, mediated by the unknown metabolite X-12730, with the highest mediation ratio of 11.1% CD4/CD8br showing a causal relationship with BC, mediated by choline levels, with a mediation ratio of 8.78%. CD19 on IgD- CD24- associated with BC, mediated by 4-vinylphenol sulfate levels, with a mediation ratio of 10.9%. CD19 on IgD- CD27- was linked to BC, mediated by ribitol levels, with a mediation ratio of 6.58%. CD38 on IgD+ CD24- B cells was associated with BC, mediated by pimeloylcarnitine/3-methyladipoylcarnitine (C7-DC) levels, with a mediation ratio of 6.73%. This study identified 5 immune cell phenotypes that are causally associated with BC, mediated through 5 plasma metabolites. These findings enhance our understanding of the biological pathways involved, provide potential biomarkers for identifying at-risk populations, and offer insights into strategies for early prevention and diagnosis of BC.