The role of lipid-lowering drugs in urologic and male reproductive cancers: a Mendelian randomization study.

BACKGROUND: Urologic and male reproductive system tumors are common in older men and frequently coexist with cardiovascular and metabolic disorders, suggesting potential shared biological pathways. Although lipid-lowering therapies are widely used for cardiovascular prevention, their long-term associations with these cancers remain incompletely understood. We therefore applied a drug-target Mendelian randomization (MR) framework to evaluate the associations between genetically proxied lipid-lowering targets and the risks of urologic and male reproductive cancers.

METHODS: We performed a drug-target MR analysis using significant cis-expression quantitative trait loci for lipid-lowering drug target genes from the Genotype-Tissue Expression (GTEx v8) dataset (n=838) as genetic instruments. Single-nucleotide polymorphism (SNP) associations with lipid traits were obtained from the UK Biobank, including low-density lipoprotein cholesterol (LDL-C; n=440,546) and triglycerides (TGs; n=441,016), and colocalization analysis was used to prioritize robust target genes. Outcome data were derived from FinnGen in predominantly European populations, including bladder cancer (2,053 cases and 287,137 controls), renal cell carcinoma (2,223 cases and 287,137 controls), prostate cancer (13,216 cases and 119,948 controls), carcinoma of the renal pelvis (125 cases and 287,137 controls), and testicular cancer (407 cases and 119,948 controls). Causal effects were primarily estimated using the inverse-variance weighted (IVW) method, with additional sensitivity analyses to assess pleiotropy, heterogeneity, and robustness. For external validation of the causal associations, we repeated the drug-target MR analyses using Global Lipids Genetics Consortium (GLGC) lipid summary statistics instead of the UK Biobank data, while retaining the same tumor outcome datasets. Coronary artery disease (CAD) was included as a positive control outcome.

RESULTS: Genetically proxied inhibition of ANGPTL3 was associated with a higher risk of prostate cancer [odds ratio (OR) =1.365; 95% confidence interval (CI): 1.091-1.709], whereas genetically proxied inhibition of HMGCR (OR =0.718; 95% CI: 0.559-0.924) and NPC1L1 (OR =0.274; 95% CI: 0.137-0.550) was associated with a lower risk. For bladder cancer, inhibition of LPL (OR =1.455; 95% CI: 1.136-1.863) and PCSK9 (OR =1.757; 95% CI: 1.151-2.684) was associated with increased risk. ANGPTL3 inhibition was also associated with an increased risk of renal cell carcinoma (OR =1.975; 95% CI: 1.217-3.205). In testicular cancer, inhibition of NPC1L1 (OR =0.017; 95% CI: 0.001-0.295) and APOB (OR =0.197; 95% CI: 0.089-0.438) was associated with reduced risk. These associations remained statistically significant after multiple-testing correction (all q <0.05). Sensitivity analyses showed no evidence of directional horizontal pleiotropy, no substantial heterogeneity based on Cochran's Q test, and generally robust estimates in leave-one-out analyses. Key associations were further supported in validation analyses using GLGC lipid summary statistics.

CONCLUSIONS: This study provides genetic evidence that lipid-lowering drug targets may have heterogeneous associations with urologic and male reproductive system cancers, supporting long-term pharmacological safety monitoring and further mechanistic and genetic validation.