A multilocus approach to the antihypertensive pharmacogenetics of hydrochlorothiazide.

 
TitleA multilocus approach to the antihypertensive pharmacogenetics of hydrochlorothiazide.
Publication TypeJournal Article
Year of Publication2005
Authorsvan der Zee, A-HMaitland-, Turner, ST, Schwartz, GL, Chapman, AB, Klungel, OH, Boerwinkle, E
JournalPharmacogenet Genomics
Volume15
Issue5
Pagination287-93
Date Published2005 May
ISSN1744-6872
KeywordsAntihypertensive Agents, Blood Pressure, Cytochrome P-450 CYP11B2, Female, Humans, Hydrochlorothiazide, Male, Middle Aged, Nitric Oxide Synthase, Polymorphism, Genetic, Sodium Channels
Abstract

OBJECTIVES: To assess the influence of variations in multiple candidate genes on inter-individual variation in diastolic blood pressure (DBP) response to hydrochlorothiazide.METHODS: A community-based sample of 585 adults with essential hypertension underwent monotherapy with hydrochlorothiazide for 4 weeks. In a nested case-control design, 195 individuals in the highest tertile of DBP response (responders) and 195 individuals in the lowest tertile of DBP response (non-responders) were genotyped for 45 polymorphisms in 19 candidate genes. For those polymorphisms where the set association approach found to be significantly associated with DBP response, logistic regression was performed to estimate the odds ratio (OR) for response associated variation in the identified genotype/haplotype.RESULTS: Two polymorphisms in the sodium channel gamma-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were significantly associated with blood pressure response to hydrochlorothiazide. In the final experiment for the set association model P=0.038. In the logistic regression analyses, compared to subjects with the CT/CT haplotype of the SCNN1G gene, those with the GA/GA haplotype had OR 5.21 of being a DBP responder [95% CI 1.65-16.47]. Compared to subjects with the GT genotype of the ENOSA_rs1799983 polymorphism, those with the GG genotype had an OR 2.19 of being a DBP responder [95% CI 1.27-3.77].CONCLUSIONS: Two polymorphisms in the sodium channel gamma-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were associated with significant differences in odds of DBP response to hydrochlorothiazide. Follow-up studies are needed to define the functional genetic variations and their mechanisms of pharmacogenetic effects.

Alternate JournalPharmacogenet. Genomics
PubMed ID15864129
Grant ListM01-RR00039 / RR / NCRR NIH HHS / United States
M01-RR00585 / RR / NCRR NIH HHS / United States
R01 HL5330 / HL / NHLBI NIH HHS / United States