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Lookup NU author(s): Dr Stephen WhiteORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022 The Authors. Background: DNA hypomethylation at the F2RL3 (F2R like thrombin or trypsin receptor 3) locus has been associated with both smoking and atherosclerotic cardiovascular disease; whether these smoking-related associations form a pathway to disease is unknown. F2RL3 encodes protease-activated receptor 4, a potent thrombin receptor expressed on platelets. Given the role of thrombin in platelet activation and the role of thrombus formation in myocardial infarction, alterations to this biological pathway could be important for ischemic cardiovascular disease. Methods: We conducted multiple independent experiments to assess whether DNA hypomethylation at F2RL3 in response to smoking is associated with risk of myocardial infarction via changes to platelet reactivity. Using cohort data (N=3205), we explored the relationship between smoking, DNA hypomethylation at F2RL3, and myocardial infarction. We compared platelet reactivity in individuals with low versus high DNA methylation at F2RL3 (N=41). We used an in vitro model to explore the biological response of F2RL3 to cigarette smoke extract. Finally, a series of reporter constructs were used to investigate how differential methylation could impact F2RL3 gene expression. Results: Observationally, DNA methylation at F2RL3 mediated an estimated 34% of the smoking effect on increased risk of myocardial infarction. An association between methylation group (low/high) and platelet reactivity was observed in response to PAR4 (protease-activated receptor 4) stimulation. In cells, cigarette smoke extract exposure was associated with a 4.9% to 9.3% reduction in DNA methylation at F2RL3 and a corresponding 1.7-(95% CI, 1.2-2.4, P=0.04) fold increase in F2RL3 mRNA. Results from reporter assays suggest the exon 2 region of F2RL3 may help control gene expression. Conclusions: Smoking-induced epigenetic DNA hypomethylation at F2RL3 appears to increase PAR4 expression with potential downstream consequences for platelet reactivity. Combined evidence here not only identifies F2RL3 DNA methylation as a possible contributory pathway from smoking to cardiovascular disease risk but from any feature potentially influencing F2RL3 regulation in a similar manner.
Author(s): Corbin LJ, White SJ, Taylor AE, Williams CM, Taylor K, Van Den Bosch MT, Teasdale JE, Jones M, Bond M, Harper MT, Falk L, Groom A, Hazell GGJ, Paternoster L, Munafo MR, Nordestgaard BoG, Tybjaerg-Hansen A, Bojesen SE, Relton C, Min JL, Davey Smith G, Mumford AD, Poole AW, Timpson NJ
Publication type: Article
Publication status: Published
Journal: Circulation Research
Year: 2022
Volume: 130
Issue: 3
Pages: 384-400
Print publication date: 04/02/2022
Online publication date: 11/01/2022
Acceptance date: 04/01/2022
Date deposited: 08/11/2023
ISSN (print): 0009-7330
ISSN (electronic): 1524-4571
Publisher: Lippincott Williams and Wilkins
URL: https://doi.org/10.1161/CIRCRESAHA.121.318836
DOI: 10.1161/CIRCRESAHA.121.318836
PubMed id: 35012325
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