{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T02:13:45Z","timestamp":1784772825649,"version":"3.55.0"},"reference-count":47,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,8,15]],"date-time":"2021-08-15T00:00:00Z","timestamp":1628985600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K01 HL141690"],"award-info":[{"award-number":["K01 HL141690"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:p>We sought to identify genome\u2010wide 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\u2010wide antihypertensive drug\u2010single nucleotide polymorphism (SNP) interaction tests for four drug classes (\u03b2\u2010blockers, <jats:italic>n<\/jats:italic>\u00a0=\u00a09,195; calcium channel blockers (CCBs), <jats:italic>n<\/jats:italic>\u00a0=\u00a010,511; thiazide\/thiazide\u2010like diuretics, <jats:italic>n<\/jats:italic>\u00a0=\u00a03,516; ACE\u2010inhibitors\/ARBs, <jats:italic>n<\/jats:italic>\u00a0=\u00a02,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta\u2010analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (<jats:italic>n<\/jats:italic>\u00a0=\u00a021,267), blood pressure (BP) response in independent ICAPS studies (<jats:italic>n<\/jats:italic>\u00a0=\u00a01,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; <jats:italic>n<\/jats:italic>\u00a0=\u00a05,115). One signal reached genome\u2010wide significance in the \u03b2\u2010blocker\u2010SNP interaction analysis (rs139945292, Interaction <jats:italic>P<\/jats:italic>\u00a0=\u00a01.56\u00a0\u00d7\u00a010<jats:sup>\u22128<\/jats:sup>). rs139945292 was validated through BP response to \u03b2\u2010blockers, with the T\u2010allele associated with less BP reduction (systolic BP response <jats:italic>P<\/jats:italic>\u00a0=\u00a06\u00a0\u00d7\u00a010<jats:sup>\u22124<\/jats:sup>, Beta\u00a0=\u00a03.09, diastolic BP response <jats:italic>P<\/jats:italic>\u00a0=\u00a05\u00a0\u00d7\u00a010<jats:sup>\u22123<\/jats:sup>, Beta\u00a0=\u00a01.53). The T\u2010allele was also associated with increased adverse cardiovascular risk within the \u03b2\u2010blocker treated patients\u2019 subgroup (<jats:italic>P<\/jats:italic>\u00a0=\u00a02.35\u00a0\u00d7\u00a010<jats:sup>\u22124<\/jats:sup>, odds ratio\u00a0=\u00a01.57, 95% confidence interval\u00a0=\u00a01.23\u20131.99). The locus showed nominal replication in CHARGE, and consistent directional trends in \u03b2\u2010blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50\u00a0kb upstream gene <jats:italic>NTM<\/jats:italic> (neurotrimin). No SNPs attained genome\u2010wide significance for any other drugs classes. Top SNPs were located near <jats:italic>CALB1<\/jats:italic> (CCB), <jats:italic>FLJ367777<\/jats:italic> (ACE\u2010inhibitor), and <jats:italic>CES5AP1<\/jats:italic> (thiazide). The <jats:italic>NTM<\/jats:italic> region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in \u03b2\u2010blocker treated patients. Further investigation into this region is warranted.<\/jats:p>","DOI":"10.1002\/cpt.2355","type":"journal-article","created":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T08:08:20Z","timestamp":1625645300000},"page":"723-732","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Adverse Cardiovascular Outcomes and Antihypertensive Treatment: A Genome\u2010Wide Interaction Meta\u2010Analysis in the International Consortium for Antihypertensive Pharmacogenomics Studies"],"prefix":"10.1111","volume":"110","author":[{"given":"Caitrin W.","family":"McDonough","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine College of Pharmacy University of Florida Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen 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Clinical Surgical and Experimental Science University of Sassari Medical School Sassari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo P.","family":"Hiltunen","sequence":"additional","affiliation":[{"name":"Department of Medicine and Research Program for Clinical and Molecular Metabolism University of Helsinki and Helsinki University Hospital Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimmo K.","family":"Kontula","sequence":"additional","affiliation":[{"name":"Department of Medicine and Research Program for Clinical and Molecular Metabolism University of Helsinki and Helsinki University Hospital Helsinki Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna K.","family":"Arnett","sequence":"additional","affiliation":[{"name":"College of Public Health Dean\u2019s Office University of Kentucky Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John 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