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; Mendelson, Michael M.; Ward-Caviness, Cavin K.; Joehanes, Roby; Huan, TianXiao; Gondalia, Rahul; Salfati, Elias; Brody, Jennifer A.; Fiorito, Giovanni; Bressler, Jan; Chen, Brian H.; Ligthart, Symen; Guarrera, Simonetta; Colicino, Elena; Just, Allan C.; Wahl, Simone; Gieger, Christian; Vandiver, Amy R.; Tanaka, Toshiko; Hernandez, Dena G.; Pilling, Luke C.; Singleton, Andrew B.; Sacerdote, Carlotta; Krogh, Vittorio; Panico, Salvatore; Tumino, Rosario; Li, Yun; Zhang, Guosheng; Stewart, James D.; Floyd, James S.; Wiggins, Kerri L.; Rotter, Jerome; Multhaup, Michael; Bakulski, Kelly; Horvath, Steven; Tsao, Philip S.; Absher, Devin M.; Vokonas, Pantel; Hirschhorn, Joel; Fallin, M. Daniele; Liu, Chunyu; Bandinelli, Stefania; Boerwinkle, Eric; Dehghan, Abbas; Schwartz, Joel D.; Psaty, Bruce M.; Feinberg, Andrew P.; Hou, Lifang; Ferrucci, Luigi; Sotoodehnia, Nona; Matullo, Giuseppe; Peters, Annette ; Fornage, Myriam; Assimes, Themistocles L.; Whitsel, Eric A.; Levy, Daniel; Baccarelli, Andrea A. (2019): 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. In: Circulation, Vol. 140, No. 8: pp. 645-657

Abstract

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.

• Item Type: Journal article
• Faculties: Medicine; Medicine > Institute for Medical Information Processing, Biometry and Epidemiology
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 0009-7322
• Language: English