Genomic Association of Single Nucleotide Polymorphisms with Blood Pressure Response to Hydrochlorothiazide among South African Adults with Hypertension

Abstract

This study described single nucleotide polymorphisms (SNPs) in hydrochlorothiazide-associated genes and further assessed their correlation with blood pressure control among South African adults living with hypertension. A total of 291 participants belonging to the Nguni tribes of South Africa on treatment for hypertension were recruited. Nineteen SNPs in hydrochlorothiazide pharmacogenes were selected and genotyped using MassArray. Uncontrolled hypertension was defined as blood pressure ≥140/90 mmHg. The association between genotypes, alleles and blood pressure response to treatment was determined by conducting multivariate logistic regression model analysis. The majority of the study participants were female (73.19%), Xhosa (54.98%) and had blood pressure ≥140/90 mmHg (68.73%). Seventeen SNPs were observed among the Xhosa tribe, and two (rs2070744 and rs7297610) were detected among Swati and Zulu participants. Furthermore, alleles T of rs2107614 (AOR = 6.69; 95%CI 1.42–31.55; p = 0.016) and C of rs2776546 (AOR = 3.78; 95%CI 1.04–13.74; p = 0.043) were independently associated with uncontrolled hypertension, whilst rs2070744 TC (AOR = 38.76; 95%CI 5.54–270.76; p = 0.00023), CC (AOR = 10.44; 95%CI 2.16–50.29; p = 0.003) and allele T of rs7297610 (AOR = 1.86; 95%CI 1.09–3.14; p = 0.023) were significantly associated with uncontrolled hypertension among Zulu and Swati participants. We confirmed the presence of SNPs associated with hydrochlorothiazide, some of which were significantly associated with uncontrolled hypertension in the study sample. Findings open doors for further studies on personalized therapy for hypertension in the country.

Pharmacogenomics of Hypertension in Africa: Paving the Way for a Pharmacogenetic-Based Approach for the Treatment of Hypertension in Africans

“…In a study by Turner et al [ 102 ], ADBR2 rs2400707G>A was reported to cause a significant reduction in ambulatory SBP, but not DBP, among the study participants who included Africans. The same SNP was also studied by Masilela et al among South African Nguni tribes [ 103 ]. In this study, they show that A-allele carriers exhibited better BP control and were less likely to develop uncontrolled hypertension.…”

“…In this study, the rs1159744 G>C was associated with the greatest decrease in ambulatory BP responses to HCT and was also associated with significant differences in urinary potassium excretion. A study by Masilela et al, among Nguni South African patients on HCT, reported an association of the WNK1 rs2107614 SNP with uncontrolled hypertension (>140/90 mmHg) [ 103 ].…”

“…Gene expression analyses also showed that CC homozygotes had higher YEATS4 levels which decreased by 15% after HCT treatment further demonstrating the pharmacogenomic effect of the chromosome 12q locus. Masilela et al [ 103 ] also reported on the rs7297610 SNP uncovered by GWAS. In this study, the T allele was found to be associated with uncontrolled hypertension among Swati and Zulu participants, while C allele carriers were less likely to have uncontrolled hypertension further confirming previous findings by Turner et al [ 129 , 130 ].…”

Global interventions in hypertension: new and emerging concepts

“…In a European Mendelian randomization, modifiable risk factors such as obesity, salt intake, body mass index, alcohol dependence, smoking, coffee consumption, physical activity, sleep duration, and educational factors were found to be causal HTN risk factors [40]. A study of 291 Black South Africans confirmed the presence of SNPs associated with hydrochlorothiazide, some of which were significantly linked to uncontrolled HTN and suggests the need for further investigation of personalized therapy [41]. Furthermore, among self-reported Blacks in Systolic Blood Pressure Intervention Trial (SPRINT), a higher proportion of West African ancestry was associated with a modestly lower risk for CVD events, suggesting that extrinsic and structural societal factors, more than genetic ancestry, may be the major drivers of disparate CVD with HTN in African Americans [42].…”

Genetic Factors Contributing to the Pathogenesis of Essential Hypertension in Two African Populations

“…To date, no genetic association with EH has been described in South African cohorts [ 18 , 35 , 36 ], though genetic associations in distinct South African ethnic groups have been described with blood pressure traits [ 37 , 38 ] and uncontrolled hypertension [ 16 , 39 , 40 ]. South Africa, with its rich ethnic diversity [ 41 , 42 , 43 ], presents a unique opportunity to unearth ethnic-specific associations, shedding light on the complex interplay between genetics and EH.…”