Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide

Stephen T. Turner, Eric Boerwinkle, Jeffrey R. O'Connell, Kent R. Bailey, Yan Gong, Arlene B. Chapman, Caitrin W. McDonough, Amber L. Beitelshees, Gary L. Schwartz, John G. Gums, Sandosh Padmanabhan, Timo P. Hiltunen, Lorena Citterio, Kati M. Donner, Thomas Hedner, Chiara Lanzani, Olle Melander, Janna Saarela, Samuli Ripatti, Björn WahlstrandPaolo Manunta, Kimmo Kontula, Anna F. Dominiczak, Rhonda M. Cooper-DeHoff, Julie A. Johnson

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)391-397
Number of pages7
Issue number2
StatePublished - Aug 2013


  • Antihypertensive agents
  • Genomics
  • Hydrochlorothiazide
  • Hypertension
  • Pharmacogenomics
  • Protein kinase C

ASJC Scopus subject areas

  • Internal Medicine


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