Genetic Impact on First Line Treatment to Hypertension in Black South Africans

Abstract

Background: Systemic arterial hypertension (HT), a condition characterized by systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic BP (DBP) ≥ 90 mmHg, is the leading modifiable risk factor for cardiovascular diseases (CVD). Africa carries the largest burden of HT worldwide, with recent studies reporting prevalence as high as 48%. There is growing evidence that genetic variation can affect interindividual response to HT medications, including diuretics and calcium channel blockers which are commonly prescribed for African-ancestry patients. This adds to the HT treatment burden in Africa. This thesis therefore investigates (1) HT treatment practises in South African health primary health centres and (2) the potential role of pharmacogenetic variation in treatment response in Black South African patients. Methods: An observational prospective study on newly diagnosed hypertensives undergoing treatment at clinics in Soweto, South Africa, was conducted. Anthropometric, demographic, and clinical data were recorded at baseline and during subsequent follow up visits. Fisher’s exact and Kruskal-Wallis tests were conducted to test for associations between clinical variables and treatment subgroups. Linear mixed models for longitudinal data were used to identify predictors of blood pressure at first follow up. For the genetic analyses, targeted next generation sequencing was conducted on 16 candidate genes, selected due to their importance in the response to the first-line diuretic drug hydrochlorothiazide (HCTZ). Following variant calling, in silico tools were used to identify potentially deleterious variants. Furthermore, association tests were performed to determine potential variant signals for the response (or non-response) to treatment. Results: A total of 364 participants were included in the study having met the main criteria of at least one follow-up visit. There were more female participants compared to males and the mean age was 49 years. Combination therapy was prescribed more frequently than monotherapy, and thiazide diuretics and calcium channel blockers were the most prescribed drug classes. There was a significant decrease in the mean systolic and diastolic blood pressure between baseline and first follow up across all treatment subgroups. More than half of the study participants had controlled blood pressure at first follow up. There were clinic-specific differences in treatment strategy (regarding number of drugs and drug class prescribed) and this was reflected in the outcomes. More females had controlled blood pressure at first follow up compared to males. For the genetic analyses, a total of 1 258 variants were identified across the cohort, with 15% (188/1258) in coding regions and 7% (89/1258) being novel. Of the novel variants in coding regions, 66% (8/12) were predicted to be deleterious by at least one computational variant effect predictor. Lastly, of the eight variants previously reported to influence HCTZ response (in European, American and Asian populations), none were associated with HT treatment outcome in our study. Moreover, two of these variants (rs10995311 and rs5186) were rare in our cohort but common in the European and Asian cohorts. Discussion: This study is the first to explore the characteristics of newly diagnosed hypertensives and treatment practises at primary health care level in Soweto, South Africa. The disease landscape of HT in a community like Soweto is complex and the management vii practices adopted reflect this. The genetic variation identified in HCTZ response-related genes in this cohort exemplify the rich genetic diversity in continental Africans. While computational tools provided insights on the effects of variants across the candidate genes, the clinical functional impact, especially for predicted deleterious variants, needs to be further assessed to better understand their potential influence on response to treatment.