학술논문

Adverse Cardiovascular Outcomes and Antihypertensive Treatment: A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies.
Document Type
Academic Journal
Author
McDonough CW; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.; Warren HR; Clinical Pharmacology Department, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.; NIHR Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.; Jack JR; Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, North Carolina, USA.; Motsinger-Reif AA; Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina, USA.; Armstrong ND; Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.; Bis JC; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.; House JS; Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina, USA.; Singh S; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.; El Rouby NM; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.; Gong Y; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.; Mychaleckyj JC; Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.; Rotroff DM; Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, North Carolina, USA.; Benavente OR; Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.; Caulfield MJ; National Institute for Health Research, Barts Cardiovascular Biomedical Research Center, Queen Mary University of London, London, UK.; Doria A; Research Division, Joslin Diabetes Center; and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.; Pepine CJ; Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.; Psaty BM; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.; Department of Epidemiology, University of Washington, Seattle, Washington, USA.; Glorioso V; Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milano, Italy.; Glorioso N; Department of Clinical, Surgical and Experimental Science, University of Sassari, Medical School, Sassari, Italy.; Hiltunen TP; Department of Medicine and Research Program for Clinical and Molecular Metabolism, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Kontula KK; Department of Medicine and Research Program for Clinical and Molecular Metabolism, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Arnett DK; College of Public Health, Dean's Office, University of Kentucky, Lexington, Kentucky, USA.; Buse JB; Division of Endocrinology, Department of Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Irvin MR; Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.; Johnson JA; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.; Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.; Munroe PB; Clinical Pharmacology Department, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.; NIHR Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.; Wagner MJ; Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Cooper-DeHoff RM; Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.; Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.
Source
Publisher: Wiley Country of Publication: United States NLM ID: 0372741 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-6535 (Electronic) Linking ISSN: 00099236 NLM ISO Abbreviation: Clin Pharmacol Ther Subsets: MEDLINE
Subject
Language
English
Abstract
We sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-single nucleotide polymorphism (SNP) interaction tests for four drug classes (β-blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide-like diuretics, n = 3,516; ACE-inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome-wide significance in the β-blocker-SNP interaction analysis (rs139945292, Interaction P = 1.56 × 10 -8 ). rs139945292 was validated through BP response to β-blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 × 10 -4 , Beta = 3.09, diastolic BP response P = 5 × 10 -3 , Beta = 1.53). The T-allele was also associated with increased adverse cardiovascular risk within the β-blocker treated patients' subgroup (P = 2.35 × 10 -4 , odds ratio = 1.57, 95% confidence interval = 1.23-1.99). The locus showed nominal replication in CHARGE, and consistent directional trends in β-blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in β-blocker treated patients. Further investigation into this region is warranted.
(© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)