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

• 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
• Journal Title: Journal of the American Heart Association
• Volume: Volume 3, Number 6
• Publisher: Wiley Open Access: Creative Commons Attribution Non-Commercial | 2014-12-01, Pages e001398-e001398
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1161/JAHA.114.001398
• Subjects: Health Sciences, Pharmacology; Health Sciences, General
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cardiac & Cardiovascular Systems; Cardiovascular System & Cardiology; genetics; hypertension; pharmacology; resistant hypertension; GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; SMOOTH-MUSCLE-CELLS; HIGH-BLOOD-PRESSURE; ANTIHYPERTENSIVE RESPONSES; SUSCEPTIBILITY LOCI; PLASMA-MEMBRANE; HEART-DISEASE; METAANALYSIS; PARAOXONASE

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).