Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic

Stephen T Turner, Kent R Bailey, Brooke L. Fridley, Arlene B. Chapman, Gary Lee Schwartz, High Seng Chai, Hugues Sicotte, Jean-Pierre Kocher, Andréi S. Rodin, Eric Boerwinkle

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

We conducted a genome-wide association study to identify novel genes influencing diastolic blood pressure (BP) response to hydrochlorothiazide, a commonly prescribed thiazide diuretic preferred for the treatment of high BP. Affymetrix GeneChip Human Mapping 100K Arrays were used to measure single nucleotide polymorphisms across the 22 autosomes in 194 non-Hispanic black subjects and 195 non-Hispanic white subjects with essential hypertension selected from opposite tertiles of the race- and sex-specific distributions of age-adjusted diastolic BP response to hydrochlorothiazide (25 mg daily, PO, for 4 weeks). The black sample consisted of 97 "good" responders (diastolic BP response [mean±SD]=-18.3±4.2 mm Hg; age=47.1±6.1 years; 51.5% women) and 97 "poor" responders (diastolic BP response=-0.18±4.3; age=47.4±6.5 years; 51.5% women). Haplotype trend regression identified a region of chromosome 12q15 in which haplotypes constructed from 3 successive single nucleotide polymorphisms (rs317689, rs315135, and rs7297610) in proximity to lysozyme (LYZ), YEATS domain containing 4 (YEATS4), and fibroblast growth receptor substrate 2 (FRS2) were significantly associated with diastolic BP response (nominal P=2.39 X10 -7; Bonferroni corrected P=0.024; simulated experiment-wise P=0.040). Genotyping of 35 additional single nucleotide polymorphisms selected to "tag" linkage disequilibrium blocks in these genes provided corroboration that variation in LYZ and YEATS4 was associated with diastolic BP response in a statistically independent data set of 291 black subjects and in the sample of 294 white subjects. These results support the use of genome-wide association analyses to identify novel genes influencing antihypertensive drug responses.

Original languageEnglish (US)
Pages (from-to)359-365
Number of pages7
JournalHypertension
Volume52
Issue number2
DOIs
StatePublished - Aug 2008

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Sodium Chloride Symporter Inhibitors
Chromosomes, Human, Pair 12
Antihypertensive Agents
Blood Pressure
Single Nucleotide Polymorphism
Hydrochlorothiazide
Genome-Wide Association Study
Muramidase
Haplotypes
Genes
Sex Distribution
Linkage Disequilibrium

Keywords

  • Blood pressure
  • Diuretic
  • Genome
  • Hypertension
  • Pharmacogenetics

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic. / Turner, Stephen T; Bailey, Kent R; Fridley, Brooke L.; Chapman, Arlene B.; Schwartz, Gary Lee; Chai, High Seng; Sicotte, Hugues; Kocher, Jean-Pierre; Rodin, Andréi S.; Boerwinkle, Eric.

In: Hypertension, Vol. 52, No. 2, 08.2008, p. 359-365.

Research output: Contribution to journalArticle

Turner, Stephen T ; Bailey, Kent R ; Fridley, Brooke L. ; Chapman, Arlene B. ; Schwartz, Gary Lee ; Chai, High Seng ; Sicotte, Hugues ; Kocher, Jean-Pierre ; Rodin, Andréi S. ; Boerwinkle, Eric. / Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic. In: Hypertension. 2008 ; Vol. 52, No. 2. pp. 359-365.
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AU - Chai, High Seng

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