Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease

Golareh Agha, Michael M. Mendelson, Cavin K. Ward-Caviness, Roby Joehanes, Tian Xiao Huan, Rahul Gondalia, Elias Salfati, Jennifer A. Brody, Giovanni Fiorito, Jan Bressler, Brian H. Chen, Symen Ligthart, Simonetta Guarrera, Elena Colicino, Allan C. Just, Simone Wahl, Christian Gieger, Amy R. Vandiver, Toshiko Tanaka, Dena G. HernandezLuke C. Pilling, Andrew B. Singleton, Carlotta Sacerdote, Vittorio Krogh, Salvatore Panico, Rosario Tumino, Yun Li, Guosheng Zhang, James D. Stewart, James S. Floyd, Kerri L. Wiggins, Jerome I. Rotter, Michael Multhaup, Kelly Bakulski, Steven Horvath, Philip S. Tsao, Devin M. Absher, Pantel Vokonas, Joel Hirschhorn, M. Daniele Fallin, Chunyu Liu, Stefania Bandinelli, Eric Boerwinkle, Abbas Dehghan, Joel D. Schwartz, Bruce M. Psaty, Andrew P. Feinberg, Lifang Hou, Luigi Ferrucci, Nona Sotoodehnia, Giuseppe Matullo, Annette Peters, Myriam Fornage, Themistocles L. Assimes, Eric A. Whitsel, Daniel Levy, Andrea A. Baccarelli

Research output: Contribution to journalArticlepeer-review

124 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)645-657
Number of pages13
Issue number8
StatePublished - Aug 20 2019


  • coronary artery disease
  • coronary heart disease
  • epigenetics
  • gene expression regulation
  • genomics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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