Exploring the Associations and Mechanisms Between Antihypertensive Drugs and Urological Tumors: Insights from a Mendelian Randomization Study.

[BACKGROUND] Hypertension is a risk factor for urological tumors. However, the impact of antihypertensive drugs on these tumors is unclear.

[METHODS] We used summary statistics from genome-wide association studies (GWASs) of urological tumors, along with expression data for antihypertensive drug target genes from GWASs and eQTLGen. We employed two-sample Mendelian randomization and summary-based Mendelian randomization (SMR) to assess the associations between antihypertensive drugs, target genes, and urological tumors. Two-step MR analysis was performed to investigate the mediating role of protein in these associations. We further verified this finding through co-localization analysis and differential expression analysis. We also mined the US Food and Drug Administration Adverse Event Reporting System database and Phenome-Wide Association Study to study the adverse effects of antihypertensive drugs and their target genes.

[RESULTS] Angiotensin-II receptor antagonist, PSDs, and aldosterone antagonists increase the risk of testicular cancer. Angiotensin-converting enzyme inhibitors decrease the risk for prostate cancer. Genetically, PPARG increases the risk of testicular cancer, as confirmed by SMR (PPARG: P = 2.1×10, odds ratio [OR] 1.91; 95% confidence interval [CI] 1.11-3.30), two-sample Mendelian randomization (PPARG: P = 0.01, OR 2.74, 95% CI 1.23-6.11), co-localization analysis, and differential expression analysis. PPP1R1A and TAPBPL mediate the effects of PPARG on testicular cancer. The adverse reactions of antihypertensive drugs mainly affect the digestive system, especially digestive system tumors.

[CONCLUSION] Antihypertensive drugs and target genes are significant in the development of urological tumors and crucial for the development of treatment strategies.