Pharmacogenomics of Hypertension: A Genome-Wide, Placebo-Controlled Cross-Over Study, Using Four Classes of Antihypertensive Drugs

• Type of Material: Article
• Authors: Timo P. Hiltunen, University of Helsinki; Kati M. Donner, University of Helsinki; Antti‐Pekka Sarin, University of Helsinki; Janna Saarela, University of Helsinki; Samuli Ripatti, University of Helsinki; Arlene Chapman, Emory University; John G. Gums, University of Florida; Yan Gong, University of Florida; Rhonda M. Cooper-DeHoff, University of Florida; Francesca Frau, University of Milan; Valeria Glorioso, University of Sassari; Roberta Zaninello, University of Sassari; Erika Salvi, University of Milan; Nicola Glorioso, University of Sassari; Eric Boerwinkle, University of Florida; Stephen T. Turner, Mayo Clinic; Julie A. Johnson, University of Florida; Kimmo K. Kontula, University of Helsinki
• Language: English
• Date: 2015-01-09
• Publisher: Wiley Open Access: Creative Commons Attribution Non-Commercial
• Publication Version: Final Published Version
• Copyright Statement: © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1161/JAHA.114.001521
• Title of Journal or Parent Work: Journal of the American Heart Association
• ISSN: 2047-9980
• Volume: 4
• Issue: 1
• Start Page: e001521
• End Page: e001521
• Grant/Funding Information: The SOPHIA study was supported by the “Associazione per lo sviluppo della ricerca sull'ipertensione arteriosa e sulle malattie cardiovascolari ‐ ONLUS” for the sample collection and by the European Union (grant FP7‐HEALTH‐F4‐2007‐201550, HYPERGENES) and InterOmics (PB05 MIUR‐CNR Italian Flagship Project) for the genotyping and statistical analysis.; PEAR was supported by the National Institute of Health Pharmacogenetics Research Network grant U01‐GM074492 and the National Center for Advancing Translational Sciences under the award number UL1 TR000064 (University of Florida), UL1 TR000454 (Emory University) and UL1 TR000135 (Mayo Clinic) and funds from the Mayo Foundation.; Ripatti was supported by the Academy of Finland (251217), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and Biocentrum Helsinki.; This study was supported by grants from the Sigrid Juselius Foundation (Kontula), The Finnish Foundation for Cardiovascular Research (Kontula), and the Helsinki University Central Hospital (Kontula and Hiltunen).; The GERA study was supported by US Public Health Service Grants R01 HL074735 and R01 HL053335; the National Center for Advancing Translational Sciences under the award number UL1 TR000454 (Emory University) and UL1 TR000135 (Mayo Clinic); and funds from the Mayo Foundation.
• Keywords: drug response; Life Sciences & Biomedicine; ASSOCIATION ANALYSIS; BLOOD-PRESSURE RESPONSE; association study; NEPHRIN EXPRESSION; Cardiac & Cardiovascular Systems; HYDROCHLOROTHIAZIDE; hypertension; Science & Technology; genome-wide; LOSARTAN; TUBULE EPITHELIAL-CELLS; antihypertensive drug; DISEASE; RECEPTOR BLOCKER; PREDICTORS; METAANALYSIS; Cardiovascular System & Cardiology
• Research Categories: Health Sciences, Pharmacology; Biology, Genetics

Abstract

Background: Identification of genetic markers of antihypertensive drug responses could assist in individualization of hypertension treatment. Methods and Results: We conducted a genome‐wide association study to identify gene loci influencing the responsiveness of 228 male patients to 4 classes of antihypertensive drugs. The Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study is a double‐blind, placebo‐controlled cross‐over study where each subject received amlodipine, bisoprolol, hydrochlorothiazide, and losartan, each as a monotherapy, in a randomized order. Replication analyses were performed in 4 studies with patients of European ancestry (PEAR Study, N=386; GERA I and II Studies, N=196 and N=198; SOPHIA Study, N=372). We identified 3 single‐nucleotide polymorphisms within the ACY3 gene that showed associations with bisoprolol response reaching genome‐wide significance (P<5×10−8); however, this could not be replicated in the PEAR Study using atenolol. In addition, 39 single‐nucleotide polymorphisms showed P values of 10−5 to 10−7. The 20 top‐associated single‐nucleotide polymorphisms were different for each antihypertensive drug. None of these top single‐nucleotide polymorphisms co‐localized with the panel of >40 genes identified in genome‐wide association studies of hypertension. Replication analyses of GENRES results provided suggestive evidence for a missense variant (rs3814995) in the NPHS1 (nephrin) gene influencing losartan response, and for 2 variants influencing hydrochlorothiazide response, located within or close to the ALDH1A3 (rs3825926) and CLIC5 (rs321329) genes. Conclusions: These data provide some evidence for a link between biology of the glomerular protein nephrin and antihypertensive action of angiotensin receptor antagonists and encourage additional studies on aldehyde dehydrogenase–mediated reactions in antihypertensive drug action.