Causal relationship between renin-angiotensin system inhibitors and cancer: a two-sample, two-step Mendelian randomization study

BACKGROUND: The renin-angiotensin system (RAS), particularly the angiotensin II (AT2)/angiotensin I receptor axis, is implicated in promoting tumorigenesis. However, the causal relationship between angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) use and cancer remains controversial. This study employed a two-sample, two-step Mendelian randomization (MR) approach to investigate whether there is a causal relationship between ACEI/ARB use and various cancers, and if so, the direction and potential mechanism of this association. METHODS: Genome-wide association study (GWAS) summary statistics for ACEI/ARB use, 24 site-specific cancers, and potential mediators were obtained from the GWAS Catalog, Integrative Epidemiology Unit (IEU) OpenGWAS project, and FinnGen study. Potential causal effect were primarily estimated using the inverse variance weighted (IVW) method. Sensitivity analyses, including Cochran's Q test, MR-Egger regression, and leave-one-out analysis, were performed to assess the robustness of the findings. RESULTS: MR analyses demonstrated causal protective effects of genetically proxied ACEI/ARB use on gastric [odds ratio (OR) =0.834, P