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Olle Melander

Principal investigator

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Genomic Association Analysis of Common Variants Influencing Antihypertensive Response to Hydrochlorothiazide

Author

  • 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
  • Bjoern Wahlstrand
  • Paolo Manunta
  • Kimmo Kontula
  • Anna F. Dominiczak
  • Rhonda M. Cooper-DeHoff
  • Julie A. Johnson

Summary, in English

To identify novel genes influencing blood pressure response to thiazide diuretic therapy for hypertension, we conducted genome-wide association meta-analyses of approximate to 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, 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=3.3x10(-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=5.5x10(-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.

Department/s

  • Cardiovascular Research - Hypertension
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health

Publishing year

2013

Language

English

Pages

391-397

Publication/Series

Hypertension

Volume

62

Issue

2

Document type

Journal article

Publisher

Lippincott Williams & Wilkins

Topic

  • Cardiac and Cardiovascular Systems

Keywords

  • antihypertensive agents
  • genomics
  • hydrochlorothiazide
  • hypertension
  • pharmacogenomics
  • protein kinase C

Status

Published

Research group

  • Cardiovascular Research - Hypertension

ISBN/ISSN/Other

  • ISSN: 1524-4563