title: A Genetic Response Score for Hydrochlorothiazide Use: Insights From Genomics and Metabolomics Integration.
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 (∆SBP/∆DBP: -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.
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Shahin
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
authors.forename: Caitrin W
authors.initials: CW
authors.lastname: McDonough
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Rotroff
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
authors.forename: Amber L
authors.initials: AL
authors.lastname: Beitelshees
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Garrett
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
authors.forename: John G
authors.initials: JG
authors.lastname: Gums
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
authors.forename: Alison
authors.initials: A
authors.lastname: Motsinger-Reif
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Turner
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
authors.forename: Reginald F
authors.initials: RF
authors.lastname: Frye
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Cooper-DeHoff
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
authors.forename: Rima
authors.initials: R
authors.lastname: Kaddurah-Daouk
authors.affiliation: From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.). johnson@cop.ufl.edu.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use; D018660:Blood Pressure Monitoring, Ambulatory; D015331:Cohort Studies; D000075389:DCC Receptor; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D055106:Genome-Wide Association Study; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use*; D006973:Hypertension / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011956:Receptors, Cell Surface / Q000235:genetics*; D012720:Severity of Illness Index; D015398:Signal Transduction; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D000959:Antihypertensive Agents; D000075389:DCC Receptor; C501909:DCC protein, human; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D006852:Hydrochlorothiazide; C526223:PRKAG2 protein, human; D055372:AMP-Activated Protein Kinases; D004851:Epoxide Hydrolases; C506428:EPHX2 protein, human
keywords: genome-wide association study; hydrochlorothiazide; hypertension; metabolomics; pharmacogenetics