ADRB1 and ADRB2 antihypertensive target perturbations associated with increased clear cell renal cell carcinoma riskGenetic markers linked to blood pressure drugs raise kidney cancer risk

BackgroundAntihypertensive drug targets are associated with various cancers, but their relationship with clear cell renal cell carcinoma (CCRCC) risk remains unclear.MethodsSummary-data-based Mendelian randomization (SMR) and colocalization analyses were performed. Four antihypertensive drug targets (ACE, ADRB1, ADRB2, and SLC12A3) and CCRCC were included. Patients with CCRCC were identified from two large GWAS databases, including 752,817 and 315,137 individuals (Finnish cohorts), for the discovery and external validation analyses, respectively. Meta-analysis was conducted to integrate the results from both cohorts. Western blotting and prognostic analyses of tumor survival revealed the relationship between ADRB1 and CCRCC.ResultsADRB1 was associated with CCRCC risk in both the discovery and validation cohorts (odds ratio (OR): 1.097, per standard deviation unit (SD) change in antihypertensive drug target perturbation equivalent to 1 SD unit of decreased blood pressure; 95% confidence interval (95% CI): 1.063–1.132; P-value = 0.016) vs. OR: 1.284; 95% CI: 1.014–1.627; P-value = 0.013). ADRB2 was associated with CCRCC risk in discovery cohort (OR: 1.224; 95% CI: 1.045–1.433; P-value = 0.019). Integrated outcomes demonstrated that both ADRB1 (OR: 1.100; 95% CI: 1.066–1.135; P-value