June 11, 2013Hypertension108 citationsOpen Access
View Full PaperGenomic Association Analysis of Common Variants Influencing Antihypertensive Response to Hydrochlorothiazide
Structured PICO
Do specific genetic variants influence blood pressure response to hydrochlorothiazide in patients with primary hypertension?
P
Population
1,050 European and European American patients with primary hypertension (424 in discovery cohorts from PEAR and GERA studies, 626 in replication cohorts from Nordic Diltiazem and Genetics of Drug Responsiveness in Essential Hypertension studies)
I
Intervention
Hydrochlorothiazide therapy in carriers of specific genetic variants (e.g., rs16960228 A allele, rs2273359)
C
Comparator
Hydrochlorothiazide therapy in patients with alternative genotypes (e.g., rs16960228 GG homozygotes)
O
Outcome
Systolic and diastolic blood pressure response to hydrochlorothiazidesurrogate
Genetic variation at novel loci, such as rs16960228 in protein kinase C α, significantly influences blood pressure response to hydrochlorothiazide, highlighting potential targets for individualized antihypertensive therapy.
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 P4/4 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.