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

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.

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.

MR analyses demonstrated causal protective effects of genetically proxied ACEI/ARB use on gastric [odds ratio (OR) =0.834, P<0.001], colorectal (OR =0.900, P=0.006), lung (OR =0.928, P=0.02), breast (OR =0.942, P=0.03), and endometrial cancer (OR =0.900, P=0.006). These causal associations remained consistent in validation and sensitivity analyses. Mediation analyses indicated the causal, protective effects were partially mediated by vascular endothelial growth factor A (VEGF-A), total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C).

This MR study provides robust genetic evidence supporting a causal protective role of ACEI/ARB use in reducing the risk of gastric, colorectal, lung, breast, and endometrial cancers, which is partially mediated by VEGF-A, total cholesterol, triglycerides, LDL-C, and HDL-C.