Chybowska, A. D. et al. (2024) Epigenetic contributions to clinical risk prediction of cardiovascular disease. Circulation: Genomic and Precision Medicine, 17(1), e004265. (doi: 10.1161/CIRCGEN.123.004265) (PMID:38288591)
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Abstract
BACKGROUND: Cardiovascular disease (CVD) is among the leading causes of death worldwide. The discovery of new omics biomarkers could help to improve risk stratification algorithms and expand our understanding of molecular pathways contributing to the disease. Here, ASSIGN—a cardiovascular risk prediction tool recommended for use in Scotland—was examined in tandem with epigenetic and proteomic features in risk prediction models in ≥12 657 participants from the Generation Scotland cohort. METHODS: Previously generated DNA methylation–derived epigenetic scores (EpiScores) for 109 protein levels were considered, in addition to both measured levels and an EpiScore for cTnI (cardiac troponin I). The associations between individual protein EpiScores and the CVD risk were examined using Cox regression (ncases≥1274; ncontrols≥11 383) and visualized in a tailored R application. Splitting the cohort into independent training (n=6880) and test (n=3659) subsets, a composite CVD EpiScore was then developed. RESULTS: Sixty-five protein EpiScores were associated with incident CVD independently of ASSIGN and the measured concentration of cTnI (P<0.05), over a follow-up of up to 16 years of electronic health record linkage. The most significant EpiScores were for proteins involved in metabolic, immune response, and tissue development/regeneration pathways. A composite CVD EpiScore (based on 45 protein EpiScores) was a significant predictor of CVD risk independent of ASSIGN and the concentration of cTnI (hazard ratio, 1.32; P=3.7×10−3; 0.3% increase in C-statistic). CONCLUSIONS: EpiScores for circulating protein levels are associated with CVD risk independent of traditional risk factors and may increase our understanding of the etiology of the disease.
| Item Type: | Articles |
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| Additional Information: | This research was funded in whole, or in part, by the Wellcome Trust (104036/Z/14/Z, 108890/Z/15/Z, 220857/Z/20/Z, and 216767/Z/19/Z). For the purpose of open access, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission. A.D. Chybowska was supported by a Medical Research Council PhD Studentship in Precision Medicine with funding from the Medical Research Council Doctoral Training Program and the University of Edinburgh College of Medicine and Veterinary Medicine. D.A. Gadd was funded by the Wellcome Trust 4-Year PhD in Translational Neuroscience—Training the Next Generation of Basic Neuroscientists to Embrace Clinical Research (108890/Z/15/Z). Drs Bernabeu and Marioni were supported by the Alzheimer’s Society major project grant AS-PG-19b-010. Generation Scotland (GS) received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping and DNA methylation profiling of the GS samples were performed by the Genetics Core Laboratory at the Clinical Research Facility, The University of Edinburgh, United Kingdom, and was funded by the Medical Research Council UK and the Wellcome Trust (references 104036/Z/14/Z, 220857/Z/20/Z, and 216767/Z/19/Z). The DNA methylation profiling and analysis were supported by Wellcome Investigator Award 220857/Z/20/Z and grant 104036/Z/14/Z (principal investigator: AM McIntosh) and through funding from National Alliance for Research on Schizophrenia & Depression (reference 27404; awardee: Dr D.M. Howard) and the Royal College of Physicians of Edinburgh (Sim Fellowship; awardee: Dr H.C. Whalley). |
| Keywords: | cardiovascular diseases, multiomics, biomarkers, epigenomics, natriuretic peptide, brain |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Welsh, Professor Paul and Sattar, Professor Naveed |
| Authors: | Chybowska, A. D., Gadd, D. A., Cheng, Y., Bernabeu, E., Campbell, A., Walker, R. M., McIntosh, A. M., Wrobel, N., Murphy, L., Welsh, P., Sattar, N., Price, J. F., McCartney, D. L., Evans, K. L., and Marioni, R. E. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
| Journal Name: | Circulation: Genomic and Precision Medicine |
| Publisher: | Lippincott, Williams and Wilkins for American Heart Association |
| ISSN: | 2574-8300 |
| ISSN (Online): | 2574-8300 |
| Published Online: | 30 January 2024 |
| Copyright Holders: | Copyright: © 2024 The Authors |
| First Published: | First published in Circulation: Genomic and Precision Medicine 17(1): e004265 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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