Pharmacogenomic Genome-Wide Meta-Analysis of Blood Pressure Response to beta-Blockers in Hypertensive African Americans

• Type of Material: Article
• Authors: Yan Gong, University of Florida; Zhiying Wang, University of Texas Houston; Amber L. Beitelshees, University of Maryland; Caitrin W. McDonough, University of Florida; Taimour Y. Langaee, University of Florida; Karen Hall, University of Florida; Siegfried O. Schmidt, University of Florida; Robert W. Curry, Jr., University of Florida; John G. Gums, University of Florida; Kent R. Bailey, Mayo Clinic; Eric Boerwinkle, University of Texas Houston; Arlene B Chapman, Emory University; Stephen T. Turner, Mayo Clinic; Rhonda M. Cooper-DeHoff, University of Florida; Julie A. Johnson, University of Florida
• Language: English
• Date: 2016-03-01
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.06345
• Title of Journal or Parent Work: Hypertension
• ISSN: 0194-911X
• Volume: 67
• Issue: 3
• Start Page: 556
• End Page: 563
• Grant/Funding Information: Both PEAR studies were supported by the National Institute of Health Pharmacogenomics Research Network grant U01-GM074492 and the National Center for Advancing Translational Sciences under the award numbers UL1 TR000064 (University of Florida); UL1 TR000454 (Emory University) and UL1 TR000135 (Mayo Clinic). PEAR was also supported by funds from the Mayo Foundation.
• Keywords: Peripheral Vascular Disease; SINGLE-DRUG THERAPY; PROTHROMBOTIC STATE; STROKE; ASSOCIATION; blood pressure response; IMPACT; MECHANISMS; RENIN-ANGIOTENSIN SYSTEM; PROPRANOLOL; Science & Technology; ANTIHYPERTENSIVE AGENTS; PEAR; African Americans; pharmacogenomics; SECRETION; Life Sciences & Biomedicine; Cardiovascular System & Cardiology; -blockers; GWAS
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Medicine and Surgery

Abstract

African Americans suffer a higher prevalence of hypertension compared with other racial/ethnic groups. In this study, we performed a pharmacogenomic genome-wide association study of blood pressure (BP) response to β-blockers in African Americans with uncomplicated hypertension. Genome-wide meta-analysis was performed in 318 African American hypertensive participants in the 2 Pharmacogenomic Evaluation of Antihypertensive Responses studies: 150 treated with atenolol monotherapy and 168 treated with metoprolol monotherapy. The analysis adjusted for age, sex, baseline BP and principal components for ancestry. Genome-wide significant variants with P<5×10-8 and suggestive variants with P<5×10-7 were evaluated in an additional cohort of 141 African Americans treated with the addition of atenolol to hydrochlorothiazide treatment. The validated variants were then meta-analyzed in these 3 groups of African Americans. Two variants discovered in the monotherapy meta-analysis were validated in the add-on therapy. African American participants heterozygous for SLC25A31 rs201279313 deletion versus wild-type genotype had better diastolic BP response to atenolol monotherapy, metoprolol monotherapy, and atenolol add-on therapy: -9.3 versus -4.6, -9.6 versus -4.8, and -9.7 versus -6.4 mm Hg, respectively (3-group meta-analysis P=2.5×10-8, β=-4.42 mm Hg per variant allele). Similarly, LRRC15 rs11313667 was validated for systolic BP response to β-blocker therapy with 3-group meta-analysis P=7.2×10-8 and β=-3.65 mm Hg per variant allele. In this first pharmacogenomic genome-wide meta-analysis of BP response to β-blockers in African Americans, we identified novel variants that may provide valuable information for personalized antihypertensive treatment in this group.