Genomic Association Analysis of Common Variants Influencing Antihypertensive Response to Hydrochlorothiazide

• Type of Material: Article
• Authors: Stephen T. Turner, Mayo Clinic; Eric Boerwinkle, University of Texas Health Science Center; Jeffrey R. O'Connell, University of Maryland; Kent R. Bailey, Mayo Clinic; Yan Gong, University of Florida; Arlene B Chapman, Emory University; Caitrin W. McDonough, University of Florida; Amber L. Beitelshees, University of Maryland; Gary L. Schwartz, Mayo Clinic; John G. Gums, University of Florida; Sandosh Padmanabhan, University of Glasgow; Timo P. Hiltunen, University of Helsinki; Lorena Citterio, Univ Vita Salute San Raffaele; Kati M. Donner, University of Helsinki; Thomas Hedner, Sahlgrenska University Hospital; Chiara Lanzani, Università Vita Salute San Raffaele; Olle Melander, Lund University; Janna Saarela, University of Helsinki; Samuli Ripatti, University of Helsinki; Bjorn Wahlstrand, Sahlgrenska University Hospital; Paolo Manunta, Università Vita Salute San Raffaele; Kimmo Kontula, University of Helsinki; Anna F. Dominiczak, University of Glasgow; Rhonda M. Cooper-DeHoff, University of Florida; Julie A. Johnson, University of Florida
• Language: English
• Date: 2013-08-01
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.00436
• Title of Journal or Parent Work: Hypertension
• ISSN: 0194-911X
• Volume: 62
• Issue: 2
• Start Page: 391
• End Page: 397
• Grant/Funding Information: The Milan Italian study was supported by the Italian Ministry of Health grant RF-FSR-2008-1141719.; PEAR was supported by the National Institutes of Health Pharmacogenetics Research Network grant U01 GM074492; and the National Center for Advancing Translational Sciences under the work number: UL1 TR000064 (University of Florida); UL1 TR000454 (Emory University); and UL1 TR000135 (Mayo Clinic).; This work was also supported by grants HL086558, HL053330, and HL074735 and funds from the Mayo Foundation.; The GENRES was supported by grants from the Sigrid Juselius Foundation and the Finnish Foundation for Cardiovascular Research.; The NORDIL study was supported by a grant from the Pharmacia Corporation (Kalamazoo MI); and the genetic analyses by the following grants: British Heart Foundation (BHF) Chair CH/98001; BHF Programme RG/07/005/23633; BHF Special Project Grant SP/08/005/25115; European Union Ingenious HyperCare Consortium: Integrated Genomics, Clinical Research, and Care in Hypertension grant LSHM-C7-2006-037093; and BHF fellowship awards FS/05/095/19937 and FS/10/016/28162.
• Keywords: Cardiovascular System & Cardiology; BLOCKER; hypertension; Life Sciences & Biomedicine; antihypertensive agents; pharmacogenomics; protein kinase C; BLOOD-PRESSURE RESPONSE; hydrochlorothiazide; Peripheral Vascular Disease; POLYMORPHISM; genomics; DRUGS; Science & Technology; PREDICTORS; GENOMEWIDE ASSOCIATION; ESSENTIAL-HYPERTENSION
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pharmacology; Biology, Genetics

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.