Causal association between blood and urine biomarkers, immune cells, and bladder cancer: A Mendelian randomization and mediation analysis

Bladder cancer (BC) is influenced by genetic and environmental factors, with blood and urine biomarkers playing a critical role in its diagnosis and progression. However, establishing the causal association between these biomarkers and BC remains challenging due to confounding factors and reverse causation in traditional studies. Therefore, we conducted a Mendelian randomization (MR) analysis to assess the causal association between these biomarkers and BC. A bidirectional MR analysis was performed using pooled data from 35 blood and urine biomarkers, 731 immune cell types, and BC cases from the Genome-Wide Association of Transgenics and Circulating Metabolites study. Complementary analyses, including mediation analysis, 2-stage MR, and multivariate MR, were employed to investigate the potential mediating role of immune cells in this association. We further conducted sensitivity analyses to validate the stability and feasibility of our dataset. The analysis identified a causal association between BC and 2 biomarkers: calcium and sex hormone-binding globulin. Elevated calcium levels were associated with an increased risk of BC (inverse variance weighting: [OR] = 1.295, 95% [CI] = 1.062-1.578, P = .011), while higher sex hormone-binding globulin levels were linked to a decreased risk (inverse variance weighting: OR = 0.857, 95% CI = 0.741-0.991, P = .037). Notably, CD20 expression on IgD⁻ CD24⁻ B cells appeared to attenuate the positive association between calcium and BC. This study reinforces the association between specific blood and urine biomarkers and the risk of developing BC. It also highlights the mediating role of CD20 on IgD⁻ CD24⁻ B cells in the causal pathways linking these biomarkers to BC. These insights enhance our understanding of BC pathogenesis and may guide the development of targeted diagnostic and therapeutic strategies.