Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide

Hypertension. 2013 Aug;62(2):391-7. doi: 10.1161/HYPERTENSIONAHA.111.00436. Epub 2013 Jun 10.


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.

Keywords: antihypertensive agents; genomics; hydrochlorothiazide; hypertension; pharmacogenomics; protein kinase C.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antihypertensive Agents / therapeutic use*
  • Atenolol / therapeutic use
  • Blood Pressure / drug effects
  • Chromosomes, Human, Pair 17
  • Diuretics / therapeutic use*
  • Female
  • Genome-Wide Association Study*
  • Humans
  • Hydrochlorothiazide / therapeutic use*
  • Hypertension / drug therapy*
  • Hypertension / genetics
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Protein Kinase C-alpha / genetics
  • Transcription Factors / genetics


  • Antihypertensive Agents
  • Diuretics
  • Transcription Factors
  • negative elongation factor
  • Hydrochlorothiazide
  • Atenolol
  • PRKCA protein, human
  • Protein Kinase C-alpha