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Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure

Baudier, Claire; Fougerousse, Françoise; Asselbergs, Folkert W; Guedj, Mickael; Komajda, Michel; Kotecha, Dipak; Thomas Lumbers, R; ... Tyl, Benoît; + view all (2023) Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure. Frontiers in Cardiovascular Medicine , 10 , Article 1148931. 10.3389/fcvm.2023.1148931. Green open access

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Abstract

Background: The effects of α and ß adrenergic receptor modulation on the risk of developing heart failure (HF) remains uncertain due to a lack of randomized controlled trials. This study aimed to estimate the effects of α and ß adrenergic receptors modulation on the risk of HF and to provide proof of principle for genetic target validation studies in HF. Methods: Genetic variants within the cis regions encoding the adrenergic receptors α1A, α2B, ß1, and ß2 associated with blood pressure in a 757,601-participant genome-wide association study (GWAS) were selected as instruments to perform a drug target Mendelian randomization study. Effects of these variants on HF risk were derived from the HERMES GWAS (542,362 controls; 40,805 HF cases). Results: Lower α1A or ß1 activity was associated with reduced HF risk: odds ratio (OR) 0.83 (95% CI 0.74–0.93, P = 0.001) and 0.95 (95% CI 0.93–0.97, P = 8 × 10−6). Conversely, lower α2B activity was associated with increased HF risk: OR 1.09 (95% CI 1.05–1.12, P = 3 × 10−7). No evidence of an effect of lower ß2 activity on HF risk was found: OR 0.99 (95% CI 0.92–1.07, P = 0.95). Complementary analyses showed that these effects were consistent with those on left ventricular dimensions and acted independently of any potential effect on coronary artery disease. Conclusions: This study provides genetic evidence that α1A or ß1 receptor inhibition will likely decrease HF risk, while lower α2B activity may increase this risk. Genetic variant analysis can assist with drug development for HF prevention.

Type: Article
Title: Unraveling the relationships between alpha- and beta-adrenergic modulation and the risk of heart failure
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fcvm.2023.1148931
Publisher version: https://doi.org/10.3389/fcvm.2023.1148931
Language: English
Additional information: © 2023 Baudier, Fougerousse, Asselbergs, Guedj, Komajda, Kotecha, Thomas Lumbers, Schmidt and Tyl. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: Mendelian randomization, adrenergic receptors, beta-blockers, alpha-blockers, target validation, drug
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics > Infectious Disease Informatics
URI: https://discovery.ucl.ac.uk/id/eprint/10179734
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