Large-Scale Gene-Centric Analysis Identifies Polymorphisms for Resistant Hypertension

• Type of Material: Article
• Authors: Vanessa Fontana, University of Campinas; Caitrin W. McDonough, University of Florida; Yan Gong, University of Florida; Nihal M. El Rouby, University of Florida; Ana Caroline C. Sa, University of Florida; Kent D. Taylor, Harbor UCLA Medical Center; Y. -D. Ida Chen, Harbor UCLA Medical Center; John G. Gums, University of Florida; Arlene Chapman, Emory University; Stephen T. Turner, Mayo Clinic; Carl J. Pepine, University of Florida; Julie A. Johnson, University of Florida; Rhonda M. Cooper-DeHoff, University of Florida
• Language: English
• Date: 2014-12-01
• Publisher: Wiley Open Access: Creative Commons Attribution Non-Commercial
• Publication Version: Final Published Version
• Copyright Statement: © 2014 The Authors.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1161/JAHA.114.001398
• Title of Journal or Parent Work: Journal of the American Heart Association
• ISSN: 2047-9980
• Volume: 3
• Issue: 6
• Start Page: e001398
• End Page: e001398
• Grant/Funding Information: This project was supported by NIH grants R01HL074730, and U01‐GM074492, as well as grants from the University of Florida Opportunity Fund and Abbott Pharmaceuticals. INVEST was supported by the University of Florida and grants from BASF Pharma and Abbott Laboratories.; PEAR was supported by the National Institutes of Health Pharmacogenomics 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); UL1 TR000135 (Mayo Clinic) and funds from the Mayo Foundation.
• Keywords: CORONARY-ARTERY-DISEASE; Cardiac & Cardiovascular Systems; hypertension; Science & Technology; resistant hypertension; Cardiovascular System & Cardiology; pharmacology; HIGH-BLOOD-PRESSURE; SMOOTH-MUSCLE-CELLS; HEART-DISEASE; PARAOXONASE; Life Sciences & Biomedicine; genetics; PLASMA-MEMBRANE; ANTIHYPERTENSIVE RESPONSES; METAANALYSIS; GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI
• Research Categories: Health Sciences, Pharmacology; Health Sciences, General

Abstract

Background: Resistant hypertension (RHTN), defined by lack of blood pressure (BP) control despite treatment with at least 3 antihypertensive drugs, increases cardiovascular risk compared with controlled hypertension. Yet, there are few data on genetic variants associated with RHTN. Methods and Results: We used a gene-centric array containing ≈50 000 single-nucleotide polymorphisms (SNPs) to identify polymorphisms associated with RHTN in hypertensive participants with coronary artery disease (CAD) from INVEST-GENES (the INnternational VErapamil-SR Trandolapril STudy-GENEtic Substudy). RHTN was defined as BP≥140/90 on 3 drugs, or any BP on 4 or more drugs. Logistic regression analysis was performed in European Americans (n=904) and Hispanics (n=837), using an additive model adjusted for age, gender, randomized treatment assignment, body mass index, principal components for ancestry, and other significant predictors of RHTN. Replication of the top SNP was conducted in 241 European American women from WISE (Women's Ischemia Syndrome Evaluation), where RHTN was defined similarly. To investigate the functional effect of rs12817819, mRNA expression was measured in whole blood. We found ATP2B1 rs12817819 associated with RHTN in both INVEST European Americans (P-value=2.44 × 10^-3, odds ratio=1.57 [1.17 to 2.01]) and INVEST Hispanics (P=7.69 × 10^-4, odds ratio=1.76 [1.27 to 2.44]). A consistent trend was observed at rs12817819 in WISE, and the INVEST-WISE meta-analysis result reached chip-wide significance (P=1.60 × 10^-6, odds ratio=1.65 [1.36 to 1.95]). Expression analyses revealed significant differences in ATP2B1 expression by rs12817819 genotype. Conclusions: The ATP2B1 rs12817819 A allele is associated with increased risk for RHTN in hypertensive participants with documented CAD or suspected ischemic heart disease. Clinical Trial Registration: URL: www.clinicaltrials.gov; Unique identifiers: NCT00133692 (INVEST), NCT00000554 (WISE).