Potential therapeutic targets for bladder cancer: a proteome-wide Mendelian randomization study

The incidence of bladder cancer (BCa) is increasing worldwide and the development of drug targets for BCa is necessary. We conducted a proteome-wide association study (PWAS) mainly using mendelian randomization (MR) to explore the causal proteins associated with BCa. Protein quantitative trait locis (pQTLs) were derived from two large proteome genome-wide association studies. After validation by multiple sensitivity analysis and two replication analyses, we identified five plasma proteins showed significant causal associations with BCa. Our study indicated that GSTM4 (OR = 0.81 (0.74-0.89), P = 5.14 × 10^-6, PPH4 = 0.89) emerged as the most reliable target. Besides, PSCA, LY6D, SLURP1 and GSTM1 also showed clear causal association but only failed in colocalization. We also performed several downstream analyses. Protein-protein interactions analysis found these causal targets came from glutathione S-transferase family or lymphocyte antigen-6 family. Phenome-wide MR analysis revealed PSCA may lead to peptic ulcer and local infections of skin and subcutaneous tissue. We then employed single-cell analysis, protein-protein interactions, and druggability evaluation. Phenome-wide MR analysis was to assess the possible side effects of these drug targets. Finally, the reliability of GSTM4 in BCa was confirmed via colony formation assay.