Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide

Abstract

To identify novel genes influencing blood pressure response to thiazide diuretic therapy for hypertension, we conducted genome-wide association meta-analyses of ≈1.1 million single-nucleotide polymorphisms in a combined sample of 424 European Americans with primary hypertension treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses study (n=228) and the Genetic Epidemiology of Responses to Antihypertensive study (n=196). Polymorphisms associated with blood pressure response at P<10(-5) were tested for replication of the associations in independent samples of hydrochlorothiazide-treated European hypertensives. The rs16960228 polymorphism in protein kinase C, α replicated for same-direction association with diastolic blood pressure response in the Nordic Diltiazem study (n=420) and the Genetics of Drug Responsiveness in Essential Hypertension study (n=206), and the combined 4-study meta-analysis P value achieved genome-wide significance (P=3.3 × 10(-8)). Systolic or diastolic blood pressure responses were consistently greater in carriers of the rs16960228 A allele than in GG homozygotes (>4/4 mm Hg) across study samples. The rs2273359 polymorphism in the GNAS-EDN3 region also replicated for same-direction association with systolic blood pressure response in the Nordic Diltiazem study, and the combined 3-study meta-analysis P value approached genome-wide significance (P=5.5 × 10(-8)). The findings document clinically important effects of genetic variation at novel loci on blood pressure response to a thiazide diuretic, which may be a basis for individualization of antihypertensive drug therapy and identification of new drug targets.

Keywords: antihypertensive agents; genomics; hydrochlorothiazide; hypertension; pharmacogenomics; protein kinase C.

Figure 1

Manhattan plots and quantile-quantile plots from meta-analysis of genome-wide association analysis results for blood pressure response to hydrochlorothiazide in European American PEAR and GERA study participants.

Figure 2

Plot of blood pressure response to hydrochlorothiazide by chromosome 17 rs16960228 genotype of participants from five independent studies. Panel A: diastolic blood pressure response; Panel B: systolic blood pressure response. The blood pressure responses are adjusted for pretreatment blood pressure levels, age, and sex and p-values are for contrast of adjusted means between genotype groups.

Figure 3

Plot of blood pressure response to hydrochlorothiazide by chromosome 20 rs2273359 genotype of participants from three independent studies. Panel A: systolic blood pressure response; Panel B: diastolic blood pressure response. The blood pressure responses responses are adjusted for pretreatment blood pressure levels, age, and sex and p-values are for contrast of adjusted means between genotype groups.

Figure 4

Plot of relative gene expression of PRKCA by rs16960228 genotype in whole blood collected from European American PEAR Study participants at baseline prior to HCT treatment. Expression data were normalized to beta-2 microglobulin; error bars indicate standard error of mean.