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Blood leukocyte DNA methylation predicts risk of future myocardial infarction and coronary heart disease: A longitudinal study of 11,461 participants from population-based cohorts.
Circulation 140, 645-657 (2019)
Publ. Version/Full Text Research data DOI
Background: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. Methods: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. Results: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. Conclusion: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Coronary Artery Disease ; Coronary Heart Disease ; Epigenetics ; Genomics ; Gene Expression Regulation; Genome-wide Association; Cardiovascular-disease; Biased Selection; Artery-disease; Metaanalysis; Hypomethylation; Insulin; Stroke; Genes; Model
ISSN (print) / ISBN 0009-7322
Quellenangaben Volume: 140, Issue: 8, Pages: 645-657
Publisher Lippincott Williams & Wilkins
Publishing Place Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)