title: Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide.
abstract: 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.
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA. turner.stephen@mayo.edu
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Turner
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: O'Connell
authors.forename: Kent R
authors.initials: KR
authors.lastname: Bailey
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.forename: Caitrin W
authors.initials: CW
authors.lastname: McDonough
authors.forename: Amber L
authors.initials: AL
authors.lastname: Beitelshees
authors.forename: Gary L
authors.initials: GL
authors.lastname: Schwartz
authors.forename: John G
authors.initials: JG
authors.lastname: Gums
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: Timo P
authors.initials: TP
authors.lastname: Hiltunen
authors.forename: Lorena
authors.initials: L
authors.lastname: Citterio
authors.forename: Kati M
authors.initials: KM
authors.lastname: Donner
authors.forename: Thomas
authors.initials: T
authors.lastname: Hedner
authors.forename: Chiara
authors.initials: C
authors.lastname: Lanzani
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.forename: Janna
authors.initials: J
authors.lastname: Saarela
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.forename: Björn
authors.initials: B
authors.lastname: Wahlstrand
authors.forename: Paolo
authors.initials: P
authors.lastname: Manunta
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
authors.forename: Anna F
authors.initials: AF
authors.lastname: Dominiczak
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Cooper-DeHoff
authors.forename: Julie A
authors.initials: JA
authors.lastname: Johnson
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001262:Atenolol / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002886:Chromosomes, Human, Pair 17; D004232:Diuretics / Q000627:therapeutic use*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051571:Protein Kinase C-alpha / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000959:Antihypertensive Agents; D004232:Diuretics; D014157:Transcription Factors; C118437:negative elongation factor; D006852:Hydrochlorothiazide; D001262:Atenolol; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha
keywords: antihypertensive agents; genomics; hydrochlorothiazide; hypertension; pharmacogenomics; protein kinase C