pQTL Mendelian randomization analysis combined with single-cell sequencing to identify biomarkers and drug targets...

Despite the development and application of numerous biomarkers and targeted therapeutic approaches for bladder cancer, substantial limitations and challenges persist in its early diagnosis and targeted treatment. As a result, there is an immediate necessity to discover novel biomarkers and develop new targeted drugs. In the present study the association between genes and bladder cancer was analyzed through Mendelian randomization (MR). Sensitivity analysis was conducted to evaluate the reliability of gene causality. Colocalization analysis was used to reduce confounding factors due to linkage disequilibrium and improve the accuracy of causal inference. Validation was performed using quantitative polymerase chain reaction (qPCR) in bladder cancer cell lines. A nomogram model was constructed, and drug sensitivity analysis and single-cell expression typing were conducted to predict survival, select potential therapeutic targets, and detect specific cell types with abundant expression. The results identified seven genes whose predicted levels were associated with bladder cancer risk in the MR analysis. Elevated levels of four genes and decreased levels of three genes were associated with low risk of bladder cancer. All-trans retinoic acid-induced differentiation factor (ATRAID) and tripartite motif containing 25 (TRIM25) showed colocalization with SNP.PP.H4 values >0.95, indicating a high likelihood of association with bladder cancer risk. Reverse transcription qPCR validation revealed low expression of ATRAID and TRIM25 in bladder cancer. ATRAID is primarily expressed in fibroblasts and smooth muscle cells, while TRIM25 is highly expressed in endothelial cells. Using clinical data from patients, a model based on ATRAID and TRIM25 demonstrated excellent predictive performance. Furthermore, drug analysis revealed that the expression of ATRAID and TRIM25 is closely associated with the sensitivity to various chemotherapy drugs. In the present study, ATRAID and TRIM25 were identified as two biomarkers linked to the risk of bladder cancer. These findings not only provide new insights into the etiology of bladder cancer but also identify novel targets for the development of biomarkers and therapeutic medications against the disease.