A genetic response score for hydrochlorothiazide use

Mohamed H. Shahin, Yan Gong, Caitrin W. McDonough, Daniel M. Rotroff, Amber L. Beitelshees, Timothy J. Garrett, John G. Gums, Alison Motsinger-Reif, Arlene B. Chapman, Stephen T. Turner, Eric Boerwinkle, Reginald F. Frye, Oliver Fiehn, Rhonda M. Cooper-Dehoff, Rima Kaddurah-Daouk, Julie A. Johnson

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Hydrochlorothiazide is among the most commonly prescribed antihypertensives; yet, <50% of hydrochlorothiazide-treated patients achieve blood pressure (BP) control. Herein, we integrated metabolomic and genomic profiles of hydrochlorothiazide-treated patients to identify novel genetic markers associated with hydrochlorothiazide BP response. The primary analysis included 228 white hypertensives treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. Genome-wide analysis was conducted using Illumina Omni 1 mol/L-Quad Chip, and untargeted metabolomics was performed on baseline fasting plasma samples using a gas chromatography-time-of-flight mass spectrometry platform. We found 13 metabolites significantly associated with hydrochlorothiazide systolic BP (SBP) and diastolic BP (DBP) responses (false discovery rate, <0.05). In addition, integrating genomic and metabolomic data revealed 3 polymorphisms (rs2727563 PRKAG2, rs12604940 DCC, and rs13262930 EPHX2) along with arachidonic acid, converging in the netrin signaling pathway (P=1×10 -5), as potential markers, significantly influencing hydrochlorothiazide BP response. We successfully replicated the 3 genetic signals in 212 white hypertensives treated with hydrochlorothiazide and created a response score by summing their BP-lowering alleles. We found patients carrying 1 response allele had a significantly lower response than carriers of 6 alleles (ΔSBP/ΔDBP: -1.5/1.2 versus -16.3/-10.4 mm Hg, respectively, SBP score, P=1×10 -8 and DBP score, P=3×10 -9). This score explained 11.3% and 11.9% of the variability in hydrochlorothiazide SBP and DBP responses, respectively, and was further validated in another independent study of 196 whites treated with hydrochlorothiazide (DBP score, P=0.03; SBP score, P=0.07). This study suggests that PRKAG2, DCC, and EPHX2 might be important determinants of hydrochlorothiazide BP response.

Original languageEnglish (US)
Pages (from-to)621-629
Number of pages9
JournalHypertension
Volume68
Issue number3
DOIs
StatePublished - Sep 1 2016

Fingerprint

Hydrochlorothiazide
Blood Pressure
Metabolomics
Alleles
Antihypertensive Agents
Pharmacogenetics
Genetic Markers
Arachidonic Acid
Gas Chromatography
Fasting
Mass Spectrometry
Genome

Keywords

  • genome-wide association study
  • hydrochlorothiazide
  • hypertension
  • metabolomics
  • pharmacogenetics

ASJC Scopus subject areas

  • Internal Medicine
  • Medicine(all)

Cite this

Shahin, M. H., Gong, Y., McDonough, C. W., Rotroff, D. M., Beitelshees, A. L., Garrett, T. J., ... Johnson, J. A. (2016). A genetic response score for hydrochlorothiazide use. Hypertension, 68(3), 621-629. https://doi.org/10.1161/HYPERTENSIONAHA.116.07328

A genetic response score for hydrochlorothiazide use. / Shahin, Mohamed H.; Gong, Yan; McDonough, Caitrin W.; Rotroff, Daniel M.; Beitelshees, Amber L.; Garrett, Timothy J.; Gums, John G.; Motsinger-Reif, Alison; Chapman, Arlene B.; Turner, Stephen T.; Boerwinkle, Eric; Frye, Reginald F.; Fiehn, Oliver; Cooper-Dehoff, Rhonda M.; Kaddurah-Daouk, Rima; Johnson, Julie A.

In: Hypertension, Vol. 68, No. 3, 01.09.2016, p. 621-629.

Research output: Contribution to journalArticle

Shahin, MH, Gong, Y, McDonough, CW, Rotroff, DM, Beitelshees, AL, Garrett, TJ, Gums, JG, Motsinger-Reif, A, Chapman, AB, Turner, ST, Boerwinkle, E, Frye, RF, Fiehn, O, Cooper-Dehoff, RM, Kaddurah-Daouk, R & Johnson, JA 2016, 'A genetic response score for hydrochlorothiazide use', Hypertension, vol. 68, no. 3, pp. 621-629. https://doi.org/10.1161/HYPERTENSIONAHA.116.07328
Shahin MH, Gong Y, McDonough CW, Rotroff DM, Beitelshees AL, Garrett TJ et al. A genetic response score for hydrochlorothiazide use. Hypertension. 2016 Sep 1;68(3):621-629. https://doi.org/10.1161/HYPERTENSIONAHA.116.07328
Shahin, Mohamed H. ; Gong, Yan ; McDonough, Caitrin W. ; Rotroff, Daniel M. ; Beitelshees, Amber L. ; Garrett, Timothy J. ; Gums, John G. ; Motsinger-Reif, Alison ; Chapman, Arlene B. ; Turner, Stephen T. ; Boerwinkle, Eric ; Frye, Reginald F. ; Fiehn, Oliver ; Cooper-Dehoff, Rhonda M. ; Kaddurah-Daouk, Rima ; Johnson, Julie A. / A genetic response score for hydrochlorothiazide use. In: Hypertension. 2016 ; Vol. 68, No. 3. pp. 621-629.
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N2 - Hydrochlorothiazide is among the most commonly prescribed antihypertensives; yet, <50% of hydrochlorothiazide-treated patients achieve blood pressure (BP) control. Herein, we integrated metabolomic and genomic profiles of hydrochlorothiazide-treated patients to identify novel genetic markers associated with hydrochlorothiazide BP response. The primary analysis included 228 white hypertensives treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. Genome-wide analysis was conducted using Illumina Omni 1 mol/L-Quad Chip, and untargeted metabolomics was performed on baseline fasting plasma samples using a gas chromatography-time-of-flight mass spectrometry platform. We found 13 metabolites significantly associated with hydrochlorothiazide systolic BP (SBP) and diastolic BP (DBP) responses (false discovery rate, <0.05). In addition, integrating genomic and metabolomic data revealed 3 polymorphisms (rs2727563 PRKAG2, rs12604940 DCC, and rs13262930 EPHX2) along with arachidonic acid, converging in the netrin signaling pathway (P=1×10 -5), as potential markers, significantly influencing hydrochlorothiazide BP response. We successfully replicated the 3 genetic signals in 212 white hypertensives treated with hydrochlorothiazide and created a response score by summing their BP-lowering alleles. We found patients carrying 1 response allele had a significantly lower response than carriers of 6 alleles (ΔSBP/ΔDBP: -1.5/1.2 versus -16.3/-10.4 mm Hg, respectively, SBP score, P=1×10 -8 and DBP score, P=3×10 -9). This score explained 11.3% and 11.9% of the variability in hydrochlorothiazide SBP and DBP responses, respectively, and was further validated in another independent study of 196 whites treated with hydrochlorothiazide (DBP score, P=0.03; SBP score, P=0.07). This study suggests that PRKAG2, DCC, and EPHX2 might be important determinants of hydrochlorothiazide BP response.

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