Lipids, lipid-modifying drug Target genes and Bladder cancer: a Mendelian randomization study

Abstract

Abstract Background Bladder cancer (BLCA) is among the 10th most common malignancies with high morbidity and mortality. Statins and emerging lipid-modifying drug targets may also show potential in treating BLCA and lowering cholesterol levels. Mendelian randomization (MR) analysis provides insights into the causal relationship between exposure and disease. This study aimed to explore genetically predicted lipid traits, drug targets and their relationship with BLCA risk. Methods Mendelian randomization (MR) analysis was performed using genetic variants associated with lipid traits and gene variants encoding protein targets for various lipid-lowering drugs. Specific drug classes studied include HMGCR, PCSK9, NPC1L1, LDLR and APOB. For lipid-modifying drug targets that exhibited suggestive significance, cis-expression quantitative trait locus and genome-wide association study colocalization analyses were implemented to assess whether causal variants were shared. Results BLCA risk was associated with HDL (OR 1.0002, 95% CI 0.9992-1.0011, P=0.723), LDL (OR 1.0005, 95% CI 0.9997-1.0012, P=0.220), and TG (OR 1.0004, 95% CI 0.9992-1.0015, P=0.511). IVW-MR analysis observed HMGCR inhibition was significantly associated with a reduced risk of BLCA (OR 0.9954, 95% CI 0.9920-0.9988, P=0.009). Similarly, SMR analysis found that a higher expression of HMGCR was associated with a higher risk of BLCA (OR 1.0034, 95% CI 1.0006-1.0063, P=0.0179). Sensitivity analyses found no statistically significant evidence of pleiotropy or genetic confounding for bias. Conclusion In summary, this MR study demonstrated that inhibiting HMGCR may have a protective effect on BLCA, independent of the lipid-lowering effects of statins. Further research should investigate the precise mechanisms and translational potential of statins for BLCA prevention and treatment beyond cholesterol lowering.