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.
Agha, Golareh PhD ,*; Mendelson, Michael M. MD ,,,*; Ward-Caviness, Cavin K. PhD ,,*; Joehanes, Roby PhD ,,*; Huan, TianXiao PhD; Gondalia, Rahul PhD; Salfati, Elias PhD; Brody, Jennifer A. BA; Fiorito, Giovanni PhD; Bressler, Jan PhD; Chen, Brian H. PhD; Ligthart, Symen MD; Guarrera, Simonetta MSc; Colicino, Elena PhD; Just, Allan C. PhD; Wahl, Simone PhD; Gieger, Christian PhD; Vandiver, Amy R. MSc; Tanaka, Toshiko PhD; Hernandez, Dena G. PhD; Pilling, Luke C. PhD; Singleton, Andrew B. PhD; Sacerdote, Carlotta PhD; Krogh, Vittorio MD; Panico, Salvatore MD; Tumino, Rosario MD; Li, Yun PhD; Zhang, Guosheng PhD; Stewart, James D. MA; Floyd, James S. MD; Wiggins, Kerri L. MSc; Rotter, Jerome I. MD; Multhaup, Michael PhD; Bakulski, Kelly PhD; Horvath, Steven PhD; Tsao, Philip S. PhD; Absher, Devin M. PhD; Vokonas, Pantel MD; Hirschhorn, Joel MD; Fallin, M. Daniele PhD; Liu, Chunyu PhD; Bandinelli, Stefania PhD; Boerwinkle, Eric PhD; Dehghan, Abbas MD; Schwartz, Joel D. PhD; Psaty, Bruce M. MD, PhD; Feinberg, Andrew P. MD; Hou, Lifang MD; Ferrucci, Luigi MD ,+; Sotoodehnia, Nona MD ,+; Matullo, Giuseppe PhD +; Peters, Annette PhD ,,+; Fornage, Myriam Phd ,+; Assimes, Themistocles L. MD ,+; Whitsel, Eric A. MD, MPH ,+; Levy, Daniel MD ,,+; Baccarelli, Andrea A. MD ,+
140(8):645-657, August 20, 2019.
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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.
(C) 2019 by the American College of Cardiology Foundation and the American Heart Association, Inc.