Turner, S.T. et al. (2013) Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide. Hypertension, 62, pp. 391-397. (doi: 10.1161/HYPERTENSIONAHA.111.00436)
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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.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna |
Authors: | Turner, S.T., Boerwinkle, E., O'Connell, J.R., Bailey, K.R., Gong, Y., Chapman, A.B., McDonough, C.W., Beitelshees, A.L., Schwartz, G.L., Gums, J.G., Padmanabhan, S., Hiltunen, T. P., Citterio, L., Donner, K.M., Hedner, T., Lanzani, C., Melander, O., Saarela, J., Ripatti, S., Wahlstrand, B., Manunta, P., Kontula, K., Dominiczak, A.F., Cooper-DeHoff, R.M., and Johnson, J.A. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
Journal Name: | Hypertension |
Publisher: | American Heart Association |
ISSN: | 0194-911X |
ISSN (Online): | 1524-4563 |
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