Hypertension pharmacogenetics and limitations in Africa - a focus on the ACE, AGTR1 and CYP2C9 genes

Hypertension affects approximately a billion people worldwide and is a major risk for adverse cardiovascular and renal outcomes, particularly in the sub-Saharan African population. Only a small number of treated hypertensive patients achieve blood pressure control. Apart from factors such as poor medication adherence, the limited efficacy of some therapies could be attributed to inter-individual genetic variability. Thus, identifying genetic markers linked to antihypertensive drug response could assist in individualizing hypertension treatment and optimizing antihypertensive regimens to provide the greatest efficacy with the lowest risk for adverse effects. The Angiotensin-converting enzyme (ACE), Angiotensin II type I receptor (AGTR1) and Cytochrome P450 family 2 subtype C member 9 (CYP2C9) genes play pivotal roles in hypertension, and several key single-nucleotide variations (SNV) in these genes are known to have substantial effects on drug response in non-African populations. Numerous research findings corroborate that genotype-targeted antihypertension treatment regimens are more successful and can reduce costs by mitigating the likelihood of serious side effects. However, these findings may not be directly applicable to African populations due to the limited number of studies conducted and increased genomic variability within African populations. Two interconnected but distinct challenges impede translation of these benefits to African populations, namely limited implementation of pharmacogenetic testing for actionable drug-gene pairs across African healthcare systems, and the underrepresentation of African genetic ancestry in global genomic datasets, which hinders the identification and validation of population-specific variants. This review explores these dual challenges by examining the pharmacogenetic landscape of hypertension, with a focus on three clinically relevant genes: ACE, AGTR1, and CYP2C9. We highlight known gene-drug interactions, population-specific data gaps, and the need for research and infrastructure development to advance precision medicine in Africa.