Male infertility and the risk of developing prostate cancer: a bidirectional two-sample Mendelian randomization study

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BACKGROUND: Although observational studies have suggested an association between male infertility and prostate cancer (PCa) risk, the causal relationship has not been established. METHODS: We conducted a bidirectional two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary data to investigate the causal relationship between male infertility and PCa. The primary analysis was performed using the inverse variance weighted (IVW) method, supplemented by three additional MR approaches. We systematically evaluated the heterogeneity and pleiotropy of the instrumental variables and employed linkage disequilibrium score regression (LDSC) to assess the genetic correlation between the two conditions. Furthermore, we incorporated factors such as obesity and prostatitis into a multivariable Mendelian randomization framework. Additionally, within the bidirectional MR framework, we explored the causal association between the expression of the PCa biomarker prostate-specific antigen (PSA) and male infertility. Finally, we employed a summary data-based Mendelian randomization (SMR) analysis to identify genes potentially involved in the pathogenesis of PCa. We then performed a preliminary analysis of the differential expression of these significant candidate genes between normal and cancerous tissues using publicly available databases. RESULTS: Based on the fundamental principles of MR, six instrumental variables for male infertility were selected for analysis with PCa. All four analytical methods (primarily the IVW method, OR = 1.0044, 95% CI = 0.9824-1.0269, P = 0.697) consistently indicated the absence of a causal association. Reverse MR analysis suggested no significant causal relationship (IVW, OR = 0.9769, 95% CI = 0.85-1.1123, P = 0.724). Sensitivity analyses, including heterogeneity tests (Cochran's Q), pleiotropy assessment (MR-Egger intercept), and leave-one-out validation, confirmed the robustness of these findings. Furthermore, LDSC indicated no significant genetic correlation between male infertility and PCa (Rg = - 0.1102, P = 0.494). After excluding the influence of other exposure factors, multivariable Mendelian randomization results suggested an independent causal effect of prostatitis on PCa risk (IVW, OR = 1.093, 95% CI = 1.0206-1.1707, P = 0.011). No significant causal association was demonstrated between PSA and male infertility (IVW, OR = 0.981, 95% CI = 0.8055-1.1942, P = 0.847). CONCLUSION: Our findings provide no evidence for a causal relationship between male infertility and PCa in either direction.

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