A multilocus approach to the antihypertensive pharmacogenetics of hydrochlorothiazide.
OBJECTIVE
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.
Maitland-van der Zee
Anke-Hilse
AH
Human Genetics Center, University of Texas Health Science Center, Houston, TX 77030, USA. a.h.maitland-vanderzee@pharm.uu.nl
Turner
Stephen T
ST
Schwartz
Gary L
GL
Chapman
Arlene B
AB
Klungel
Olaf H
OH
Boerwinkle
Eric
E
D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics*; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000235:genetics; D011110:Polymorphism, Genetic; D015222:Sodium Channels / Q000235:genetics
D000959:Antihypertensive Agents; D015222:Sodium Channels; D006852:Hydrochlorothiazide; D019001:Nitric Oxide Synthase; D019405:Cytochrome P-450 CYP11B2