Mapping Pharmacogenomic Determinants of Adverse Drug Reactions in Hypertension: A Systematic Review

Objectives: Adverse drug reactions (ADRs) to antihypertensive medications contribute to poor medication adherence and treatment discontinuation. Pharmacogenomic approaches offer a potential means of identifying genetic variants that predict ADR risks, thereby supporting more tailored antihypertensive therapy and improved tolerability. We systematically identify and synthesize available pharmacogenomic evidence for gene-drug-ADR interaction in hypertension across all major drug classes. Methods: This systematic review follows PRISMA guidelines. Five bibliographic databases were systematically searched for pharmacogenomic studies examining associations between genetic variants and adverse drug reactions in adults receiving antihypertensive therapy. Google Scholar was additionally used as a supplementary source during full-text retrieval and citation screening to identify potentially relevant peer-reviewed publications not captured by the primary database searches. Two reviewers independently screened studies, extracted data, and assessed methodological quality using the Newcastle-Ottawa Scale. The protocol was registered in PROSPERO (CRD420251247856). Results: Seven studies published between 2002 and 2024 fulfilled the inclusion criteria, encompassing populations from Pakistan, China, Russia, South Africa, Spain, South Korea, and Japan. Notably, no pharmacogenomic evidence was identified for beta-blockers, angiotensin receptor blockers, thiazide diuretics, alpha-blockers, or loop diuretics when used as antihypertensives. The studies focused on two antihypertensive medication classes: angiotensin-converting enzyme inhibitors (ACE-I) and calcium channel blockers (CCBs). Variants in BDKRB2 have significant links to ACE-I-induced cough in different populations, with individual investigations identifying other genes involved in bradykinin metabolism and signalling (MME, PTGER3) and hepatic drug transport (SLCO1B1). Associations between CCB-related peripheral edema and CYP3A5 polymorphisms were found in Chinese Han and Russian Caucasian groups. The quality of the studies varied, but two were rated as good. Conclusions: Preliminary pharmacogenomic evidence linking antihypertensive medications to ADRs is emerging but remains limited in scope and concentrated in two drug classes. These findings represent early-phase, hypothesis-generating contributions to the evidence base required for personalized medicine in hypertension pharmacotherapy. Realizing this potential will require prospective validation in diverse, multi-ethnic cohorts, standardization of ADR reporting and causality assessment, and sustained investment in pharmacogenomic implementation science.