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

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 I; 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.
Circulation; 140(8): 645-657, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31424985


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.


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.


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.


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.
Selo DaSilva