Leveraging genetic data to explore the effects of antihypertensive drugs on health outcomes

Abstract

Hypertension is a leading risk factor for chronic diseases, affecting over one-third of the population worldwide. Antihypertensive drugs play a crucial role in reducing cardiovascular morbidity and mortality, although different drug classes have varied mechanisms. Growing evidence from experiments, observational studies, and randomized controlled trials has highlighted the effects of antihypertensive drugs on various health outcomes, such as type 2 diabetes, cancer, and mental and neurodegenerative disorders. Although they are recommended for general use in polypills for older people, whether antihypertensive drugs have repurposing potential or have harmful off-target effects remains unclear. Utilizing large summary genetic datasets, I applied Mendelian randomization (MR)—which is less likely to be affected by confounding than conventional observational studies—to investigate the potential off-target effects of antihypertensive drugs on cancer and mental disorders, as well as their impact on longevity. Genetic proxies for antihypertensive drug classes were obtained from published studies, and their genetic associations with systolic blood pressure were extracted from published genome-wide association studies (GWAS). Publicly available summary statistics for cancer, mental disorders, and longevity were obtained from the Pan-cancer study and cancer consortia, Psychiatric Genomics Consortium, and a GWAS meta-analysis of the UK Biobank and LifeGen, respectively. Finally, I conducted a systematic review of published MR studies to summarize the current state of knowledge on the effects of antihypertensive drugs on different diseases. This thesis revealed a null association of genetically proxied calcium channel blockers (CCBs) with various cancers, specifically non-Hodgkin’s lymphoma, melanoma, leukemia, thyroid, rectal, pancreatic, oral cavity/pharyngeal, kidney, esophagus/stomach, colon, bladder, endometrial, cervical, breast, prostate, lung, and ovarian cancer. Genetically proxied angiotensin-converting enzyme (ACE) inhibitors were associated with an increased risk of schizophrenia in Europeans and East Asians. The thesis showed robust evidence of positive associations of genetically proxied CCBs, beta-blockers (BBs), and vasodilators with longevity. The protective effects of CCBs and BBs were particularly evident in men. Antihypertensive drug target genes CPT2, CPT1A, CACNB3, ADRB1, CACNA2D2 and EDNRA were related to increased lifespan. In proteome-wide mediation analysis among 2291 proteins, 86 were linked to increased lifespan. CDH1 protein possibly plays a mediating role between CCBs and longevity. Finally, the systematic review included 37 studies, with most studies of high quality. Strong evidence supports the protective effects of antihypertensive drugs on cardiovascular diseases. Genetically proxied ACE inhibitors showed strong protective effects on diabetes, whereas BBs showed adverse effects. Genetically proxied ACE inhibitors could increase the risk of psoriasis, schizophrenia, and Alzheimer’s disease, but they did not affect COVID-19 risk. Genetically proxied ACE inhibitors and CCBs were beneficial for kidney function and immune function, and CCBs also showed a safe profile for disorders of pregnancy. This thesis offers novel insights into the effects of major antihypertensive drugs on health. Specifically, use of BBs, CCBs and vasodilators can be considered in health policies (i.e., polypills) to reduce the burden of chronic diseases and improve lifespan for the general population. The thesis provides credible evidence for the use of antihypertensive drugs that informs clinical decision-making, pharmacovigilance, and drug repurposing for public health.