Epigenetic Regulation of F2RL3 Associates with Myocardial Infarction and Platelet Function
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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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Circulation Research |
| Vol/bind | 130 |
| Udgave nummer | 3 |
| Sider (fra-til) | 384-400 |
| Antal sider | 17 |
| ISSN | 0009-7330 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
This work was specifically supported by the Medical Research Council (MRC) Integrative Epidemiology Unit (IEU; MC_UU_12013/3). N.J. Timpson is a Wellcome Trust (WT) Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC and WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-2001), the MRC Integrative Epidemiology Unit (MC_UU_00011/1) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). N.J. Timpson, L.J. Corbin, A.E. Taylor, C. Relton, and G. Davey Smith work in the MRC IEU at the University of Bristol which is supported by the MRC (MC_UU_00011/1, MC_UU_00011/5) and the University of Bristol. C. Relton is supported by the Cancer Research UK (CRUK) Integrative Cancer Epidemiology Programme (C18281/A29019). G. Davey Smith and A.W. Poole are funded by the British Heart Foundation (BHF; AA/18/1/34219). A.W. Poole is a Wellcome Trust Investigator (219472/Z/19/Z). K. Taylor is a BHF funded PhD student (FS/17/60/33474). This study was supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol National Health Service (NHS) Foundation Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The study was supported by the NIHR Bristol Biomedical Research Unit in Cardiovascular Medicine and by BHF, grants PG/11/44/28972, FS/12/77/29887 and CH95/001. Funding was also provided by programme and project support from the BHF to AWP (RG/15/16/31758, PG/15/96/31854, PG/13/14/30023). This research was funded in whole, or in part, by the Wellcome Trust [202802/Z/16/Z]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Funding Information:
We would like to acknowledge the following people from University of Bristol for their contribution to this work: Elizabeth Aitken for her contribution to the laboratory work which is presented in the In vitro association between smoking and F2RL3 DNA hypomethylation and expression section of the methods; Ana Goncalves Soares for advice regarding statistical analysis; David Hughes for his contribution to figure generation. We are grateful to the Bristol Proteomics Facility for assistance with this work, and the expertise provided by Dr Kate Heesom and Dr Phil Lewis. This study makes use of data generated by the Blueprint Consortium. A full list of the investigators who contributed to the generation of the data is available from www.blueprint-epigenome.eu . Funding for the project was provided by the European Union’s Seventh Framework Programme (FP7/2007- 2013) under grant agreement no. 282510 - BLUEPRINT. Avon Longitudinal Study of Parents and Children (ALSPAC): We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The UK Medical Research Council and the Wellcome Trust (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. Copenhagen City Heart Study: We acknowledge participants and team of the Copenhagen City Heart Study. The Danish Heart Foundation and the Capital Region of Denmark supported the Copenhagen City Heart Study.
Publisher Copyright:
© 2022 The Authors.
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