Key result
Among 364 newly diagnosed hypertensives, carriers of the GNB3 variant rs1025450259 had significantly greater blood pressure reduction on heterogeneous treatments, but not on HCTZ monotherapy (n=103).
Why the study?
Studies investigating genetic variation in HCTZ response-related genes have been mainly conducted in European, American, and Asian populations, leaving African populations understudied despite their high hypertension burden.
Do genetic variations in hydrochlorothiazide response-related genes impact blood pressure reduction in newly diagnosed hypertensive individuals in South Africa?
Observational (n=364)
Do genetic variations in hydrochlorothiazide response-related genes impact blood pressure reduction in newly diagnosed hypertensive individuals in South Africa?
This study identifies novel genetic variants in HCTZ response-related genes in a South African population, highlighting the need for larger pharmacogenetic trials in African cohorts to advance personalized medicine.
Association with BP response under mixed regimens is hypothesis-generating; leaves open validation for pharmacogenetics in African cohorts.
Africa bears the largest burden of morbidity and mortality from hypertension (HT) and related cardiovascular diseases. Thiazide diuretics, including hydrochlorothiazide (HCTZ), are the most prescribed hypertension medicines globally due to their cost effectiveness and minimal side effects. However, studies investigating the genetic variation in HCTZ-related genes and their effect on drug response have been mainly conducted in European, American, and Asian populations. This study aimed to examine genetic variation in HCTZ response-related genes among newly diagnosed hypertensives from Soweto, South Africa, irrespective of the treatment approach, and to assess its potential impact on medication response. Using targeted NGS on 364 newly diagnosed hypertensives with at least one follow-up visit, we identified 1258 unique variants in 16 key HCTZ response genes. Among these, 89 were novel variants, of which 12 were protein-altering, including 8 predicted to be deleterious. Association analyses with 882 independent variants revealed that carriers of the intronic variant rs1025450259 in GNB3 had significantly greater reduction in BP compared to other patients on heterogeneous treatment strategies, but no significant associations were detected in the subset of individuals treated with HCTZ monotherapy only (n = 103). For variants previously associated with HCTZ response, we did not replicate prior associations (e.g., rs2611316 in ALDH1A2) but highlight important allele frequency differences across global populations. Despite the limitations, the study outcomes support the need for larger, controlled trials to assess genetic influences on HT treatment outcomes, advancing personalized medicine for African populations. This research further underscores the importance of pharmacogenetic studies in continental African populations.
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Nyamupangedengu et al. (2025) conducted an observational in Hypertension (n=364). Genetic variation in HCTZ response-related genes (e.g., rs1025450259 in GNB3) vs. Non-carriers was evaluated on Reduction in blood pressure. Among 364 newly diagnosed hypertensives, carriers of the GNB3 variant rs1025450259 had significantly greater blood pressure reduction on heterogeneous treatments, but not on HCTZ monotherapy (n=103).
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