{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T14:17:46Z","timestamp":1765808266224,"version":"3.41.2"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T00:00:00Z","timestamp":1701734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Observational investigations have provided conflicting results regarding the effect of antihypertensive drugs on the risk of COVID-19 outcomes. We intended to assess the causal effect of antihypertensive drugs on COVID-19 outcomes using drug-target Mendelian randomization (MR), mainly including angiotensin-converting enzyme inhibitors (ACEIs), \u03b2-blockers (BBs) and calcium channel blockers (CCBs).<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> We used the genetic variants (minor allele frequency &amp;gt;1%, <jats:italic>r<\/jats:italic><jats:sup>2<\/jats:sup> &amp;lt; 0.30) located within 100\u00a0k bases of each drug target gene and associated with lower systolic blood pressure (<jats:italic>p<\/jats:italic> &amp;lt; 5 \u00d7 10<jats:sup>\u22128<\/jats:sup>) as genetic proxies for antihypertensive drugs. COVID-19 outcomes included COVID-19 susceptibility (122,616 cases and 2,475,240 controls), hospitalization (32,519 cases and 206,2805 controls), and severe illness (13,769 cases and 1,072,442 controls). All studies were conducted on populations of European ancestry. MR estimates were generated using an inverse variance weighted (IVW) model.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> IVW-MR analysis observed a weak causality between CCBs and COVID-19 susceptibility (OR: 0.993, 95% CI: 0.988\u20130.999, <jats:italic>p<\/jats:italic> = 0.012). Sensitivity analysis suggested that this result was robust. No evidence was found for a link between other antihypertensive drugs and COVID-19 outcomes.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> The present study suggests that CCBs may reduce COVID-19 susceptibility in European populations.<\/jats:p>","DOI":"10.3389\/fphar.2023.1224737","type":"journal-article","created":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T04:12:31Z","timestamp":1701749551000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Association of antihypertensive drugs with COVID-19 outcomes: a drug-target Mendelian randomization study"],"prefix":"10.3389","volume":"14","author":[{"given":"Kun","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hengxing","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingwei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,12,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"749291","DOI":"10.3389\/fimmu.2021.749291","article-title":"Effects of \u0392-blockers on the sympathetic and cytokines storms in covid-19","volume":"12","author":"Al-Kuraishy","year":"2021","journal-title":"Front. Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1016\/j.ihj.2021.10.011","article-title":"Hypertension and covid-19: potential use of beta-blockers and a call for randomized evidence","volume":"73","author":"Alsagaff","year":"2021","journal-title":"Indian Heart J."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.3390\/ijms23031772","article-title":"Immunomodulatory activity of the most commonly used antihypertensive drugs-angiotensin converting enzyme inhibitors and angiotensin ii receptor blockers","volume":"23","author":"Bryniarski","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1097\/ede.0000000000000559","article-title":"Sensitivity analyses for robust causal inference from mendelian randomization analyses with multiple genetic variants","volume":"28","author":"Burgess","year":"2017","journal-title":"Epidemiology"},{"key":"B5","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1093\/ije\/dyr036","article-title":"Avoiding bias from weak instruments in mendelian randomization studies","volume":"40","author":"Burgess","year":"2011","journal-title":"Int. J. Epidemiol."},{"key":"B6","unstructured":"Covid-19 dashboard by the center for systems science and engineering (csse) at johns hopkins university (jhu)2023"},{"key":"B7","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1093\/emph\/eoaa046","article-title":"Conflicts over calcium and the treatment of covid-19","volume":"9","author":"Crespi","year":"2021","journal-title":"Evol. Med. Public Health"},{"key":"B8","doi-asserted-by":"publisher","first-page":"223","DOI":"10.2165\/00139709-200423040-00003","article-title":"Pharmacology, pathophysiology and management of calcium channel blocker and beta-blocker toxicity","volume":"23","author":"DeWitt","year":"2004","journal-title":"Toxicol. Rev."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1038\/s41588-018-0205-x","article-title":"Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits","volume":"50","author":"Evangelou","year":"2018","journal-title":"Nat. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1001\/jama.2020.11301","article-title":"Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with covid-19 diagnosis and mortality","volume":"324","author":"Fosb\u00f8l","year":"2020","journal-title":"Jama"},{"key":"B11","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1038\/s41591-021-01310-z","article-title":"Actionable druggable genome-wide mendelian randomization identifies repurposing opportunities for covid-19","volume":"27","author":"Gaziano","year":"2021","journal-title":"Nat. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1161\/hypertensionaha.120.15324","article-title":"Age and multimorbidity predict death among covid-19 patients: results of the sars-ras study of the Italian society of hypertension","volume":"76","author":"Iaccarino","year":"2020","journal-title":"Hypertension"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1002\/sim.3034","article-title":"Mendelian randomization: using genes as instruments for making causal inferences in Epidemiology","volume":"27","author":"Lawlor","year":"2008","journal-title":"Statistics Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2002108","DOI":"10.1183\/13993003.02108-2020","article-title":"Covid-19 and copd","volume":"56","author":"Leung","year":"2020","journal-title":"Eur. Respir. J."},{"key":"B15","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1038\/s41569-021-00512-9","article-title":"Acei reduces hypertension-induced hyperinflammation in covid-19","volume":"18","author":"Lim","year":"2021","journal-title":"Nat. Rev. Cardiol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"380","DOI":"10.3390\/ph15030380","article-title":"Association of amlodipine with the risk of in-hospital death in patients with covid-19 and hypertension: a reanalysis on 184 covid-19 patients with hypertension","volume":"15","author":"Loas","year":"2022","journal-title":"Pharm. (Basel)"},{"key":"B17","doi-asserted-by":"publisher","first-page":"195","DOI":"10.7326\/m20-1515","article-title":"Risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on sars-cov-2 infection in adults: a living systematic review","volume":"173","author":"Mackey","year":"2020","journal-title":"Ann. Intern Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2431","DOI":"10.1056\/NEJMoa2006923","article-title":"Renin-angiotensin-aldosterone system blockers and the risk of covid-19","volume":"382","author":"Mancia","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"2323","DOI":"10.1111\/cts.13369","article-title":"Managing endothelial dysfunction in covid-19 with statins, beta blockers, nicorandil, and oral supplements: a pilot, double-blind, placebo-controlled, randomized clinical trial","volume":"15","author":"Matli","year":"2022","journal-title":"Clin. Transl. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.chest.2021.01.073","article-title":"Dihydropyridine calcium channel blockers and the risk of severe covid-19","volume":"160","author":"Mendez","year":"2021","journal-title":"Chest"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1769","DOI":"10.1001\/jama.2020.4812","article-title":"Covid-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence?","volume":"323","author":"Patel","year":"2020","journal-title":"Jama"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2441","DOI":"10.1056\/NEJMoa2008975","article-title":"Renin-angiotensin-aldosterone system inhibitors and risk of covid-19","volume":"382","author":"Reynolds","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1161\/hypertensionaha.120.16314","article-title":"Antihypertensive drugs and covid-19 risk: a cohort study of 2 million hypertensive patients","volume":"77","author":"Semenzato","year":"2021","journal-title":"Hypertension"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e8069","DOI":"10.7759\/cureus.8069","article-title":"Nifedipine and amlodipine are associated with improved mortality and decreased risk for intubation and mechanical ventilation in elderly patients hospitalized for covid-19","volume":"12","author":"Solaimanzadeh","year":"2020","journal-title":"Cureus"},{"key":"B25","doi-asserted-by":"publisher","first-page":"2601","DOI":"10.1161\/hypertensionaha.122.19575","article-title":"Impact of arterial hypertension and use of antihypertensive pharmacotherapy on mortality in patients hospitalized due to covid-19: the cracov-hhs study","volume":"79","author":"Wojciechowska","year":"2022","journal-title":"Hypertension"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e901","DOI":"10.1093\/cid\/ciaa1592","article-title":"The effect of prior angiotensin-converting enzyme inhibitor and angiotensin receptor blocker treatment on coronavirus disease 2019 (COVID-19) susceptibility and outcome: a systematic review and meta-analysis","volume":"72","author":"Xu","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"B27","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/s41421-020-00235-0","article-title":"Calcium Channel blocker amlodipine besylate therapy is associated with reduced case fatality rate of covid-19 patients with hypertension","volume":"6","author":"Zhang","year":"","journal-title":"Cell Discov."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1671","DOI":"10.1161\/circresaha.120.317134","article-title":"Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin ii receptor blockers with mortality among patients with hypertension hospitalized with covid-19","volume":"126","author":"Zhang","year":"","journal-title":"Circ. Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e3377","DOI":"10.1002\/dmrr.3377","article-title":"Obesity and diabetes as high-risk factors for severe coronavirus disease 2019 (Covid-19)","volume":"37","author":"Zhou","year":"2021","journal-title":"Diabetes Metab. Res. Rev."},{"key":"B30","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1007\/978-1-4614-1533-6_58","article-title":"Calcium and viruses","volume-title":"Encyclopedia of metalloproteins","author":"Zhou","year":"2013"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1224737\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T04:12:36Z","timestamp":1701749556000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1224737\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,5]]},"references-count":30,"alternative-id":["10.3389\/fphar.2023.1224737"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1224737","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2023,12,5]]},"article-number":"1224737"}}