Abstract
BACKGROUND: Evidence from observational studies suggests that the association between hypertension and cancer is controversial, likely due to confounding factors and reverse causality. This study employs Mendelian randomization (MR) to investigate the causal relationship between hypertension and various cancers. METHODS: We conducted two‑sample bidirectional MR analyses using genetic variants associated with hypertension (484,598 participants) and 17 site-specific cancers from various genome-wide association studies (GWAS) including the GWAS Catalog, Integrative Epidemiology Unit OpenGWAS project, and FinnGen study. GWAS data on anti-hypertensive drugs prescription were used to explore potential mechanisms. The primary analysis employed the inverse variance weighted (IVW) method, supplemented by MR-Egger, weighted median, weighted mode, and simple mode methods. Heterogeneity and pleiotropy were assessed using Cochran's Q, the MR-Egger intercept test, the MR pleiotropy residual sum and outlier test, leave-one-out analysis, funnel plots, and MR-Robust Adjusted Profile Score analysis. Genetic instruments were selected based on genome-wide significance (P<5×10(-8)), LD clumping (r(2)<0.001, window =10,000 kb), and F-statistic >10. Single nucleotide polymorphisms (SNPs) associated with confounders (smoking or alcohol consumption) and the outcome were removed using FastTraitR. RESULTS: We identified a potential causal relationship between hypertension and a decreased risk of gastric cancer [odds ratio (OR) =0.615, 95% confidence interval (CI): 0.415-0.912, P=0.02] and colorectal cancer (OR =0.708, 95% CI: 0.516-0.971, P=0.03). MR estimates were consistent in East Asian populations (gastric cancer, OR =0.573, P=0.01; colorectal cancer, OR =0.466, P=0.001) and directionally similar in the FinnGen cohort. Reverse MR analysis indicated an inverse association of lymphoma with hypertension risk (OR =0.992, 95% CI: 0.985-1.000, P=0.044), whereas genetic predisposition to thyroid cancer was positively associated with hypertension (OR =1.008, 95% CI: 1.002-1.013, P=0.01). Further investigation identified inverse associations between gastric cancer risk and the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) (OR =0.834, P<0.001), beta-blockers (OR =0.753, P<0.001), and calcium channel blockers (CCBs) (OR =0.794, P<0.001). Similar effects were observed for colorectal cancer with ACEI/ARB (OR =0.931, P=0.03), beta-blockers (OR =0.900, P=0.01), CCB (OR =0.912, P=0.008), and diuretics (OR =0.917, P=0.03). CONCLUSIONS: Our MR analyses suggested that genetic predisposition to hypertension was associated with a reduced risk of gastric and colorectal cancer. This inverse relationship may be mediated by biological pathways that are targeted by antihypertensive drugs, highlighting a potential mechanistic link worthy of further clinical investigation.