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

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.

• Authors: 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
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 110 Issue 3 Pg. 723-732 (09 2021) ISSN: 1532-6535 [Electronic] United States
• PMID: 34231218 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.

Chemical References

• Antihypertensive Agents

Topics

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