Adverse Cardiovascular Outcomes and Antihypertensive Treatment: A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies

Caitrin W McDonough; Helen R Warren; John R Jack; Alison A Motsinger-Reif; Nicole D Armstrong; Joshua C Bis; John S House; Sonal Singh; Nihal M El Rouby; Yan Gong; Joesyf C Mychaleckyj; Daniel M Rotroff; Oscar R Benavente; Mark J Caulfield; Alessandrio Doria; Carl J Pepine; Bruce M Psaty; Valeria Glorioso; Nicola Glorioso; Timo P Hiltunen; Kimmo K Kontula; Donna K Arnett; John B Buse; Marguerite R Irvin; Julie A Johnson; Patricia B Munroe; Michael J Wagner; Rhonda M Cooper-DeHoff

doi:10.1002/cpt.2355

Adverse Cardiovascular Outcomes and Antihypertensive Treatment: A Genome-Wide Interaction Meta-Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies

Clin Pharmacol Ther. 2021 Sep;110(3):723-732. doi: 10.1002/cpt.2355. Epub 2021 Aug 15.

Authors

Caitrin W McDonough¹, Helen R Warren^{2

3}, John R Jack⁴, Alison A Motsinger-Reif⁵, Nicole D Armstrong⁶, Joshua C Bis⁷, John S House⁵, Sonal Singh¹, Nihal M El Rouby¹, Yan Gong¹, Joesyf C Mychaleckyj⁸, Daniel M Rotroff⁴, Oscar R Benavente⁹, Mark J Caulfield¹⁰, Alessandrio Doria¹¹, Carl J Pepine¹², Bruce M Psaty^{7

13}, Valeria Glorioso¹⁴, Nicola Glorioso¹⁵, Timo P Hiltunen¹⁶, Kimmo K Kontula¹⁶, Donna K Arnett¹⁷, John B Buse¹⁸, Marguerite R Irvin⁶, Julie A Johnson^{1

12}, Patricia B Munroe^{2

3}, Michael J Wagner¹⁹, Rhonda M Cooper-DeHoff^{1

12}

Affiliations

¹ Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
² Clinical Pharmacology Department, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
³ NIHR Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁴ Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, North Carolina, USA.
⁵ Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina, USA.
⁶ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁷ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
⁸ Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
⁹ Department of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁰ National Institute for Health Research, Barts Cardiovascular Biomedical Research Center, Queen Mary University of London, London, UK.
¹¹ Research Division, Joslin Diabetes Center; and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
¹² Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.
¹³ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹⁴ Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milano, Italy.
¹⁵ Department of Clinical, Surgical and Experimental Science, University of Sassari, Medical School, Sassari, Italy.
¹⁶ Department of Medicine and Research Program for Clinical and Molecular Metabolism, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
¹⁷ College of Public Health, Dean's Office, University of Kentucky, Lexington, Kentucky, USA.
¹⁸ Division of Endocrinology, Department of Medicine, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
¹⁹ Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

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.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Antihypertensive Agents / therapeutic use*
Black or African American / genetics
Blood Pressure / drug effects
Blood Pressure / genetics
Cardiovascular Diseases / chemically induced*
Cardiovascular Diseases / genetics*
Cardiovascular System / drug effects*
Drug-Related Side Effects and Adverse Reactions / etiology
Drug-Related Side Effects and Adverse Reactions / genetics*
Female
Genome-Wide Association Study / methods
Humans
Hypertension / drug therapy*
Hypertension / genetics
Male
Middle Aged
Pharmacogenomic Testing / methods
Polymorphism, Single Nucleotide / genetics

Substances

Antihypertensive Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding