TY - JOUR
T1 - Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease
AU - Agha, Golareh
AU - Mendelson, Michael M.
AU - Ward-Caviness, Cavin K.
AU - Joehanes, Roby
AU - Huan, Tian Xiao
AU - Gondalia, Rahul
AU - Salfati, Elias
AU - Brody, Jennifer A.
AU - Fiorito, Giovanni
AU - Bressler, Jan
AU - Chen, Brian H.
AU - Ligthart, Symen
AU - Guarrera, Simonetta
AU - Colicino, Elena
AU - Just, Allan C.
AU - Wahl, Simone
AU - Gieger, Christian
AU - Vandiver, Amy R.
AU - Tanaka, Toshiko
AU - Hernandez, Dena G.
AU - Pilling, Luke C.
AU - Singleton, Andrew B.
AU - Sacerdote, Carlotta
AU - Krogh, Vittorio
AU - Panico, Salvatore
AU - Tumino, Rosario
AU - Li, Yun
AU - Zhang, Guosheng
AU - Stewart, James D.
AU - Floyd, James S.
AU - Wiggins, Kerri L.
AU - Rotter, Jerome I.
AU - Multhaup, Michael
AU - Bakulski, Kelly
AU - Horvath, Steven
AU - Tsao, Philip S.
AU - Absher, Devin M.
AU - Vokonas, Pantel
AU - Hirschhorn, Joel
AU - Fallin, M. Daniele
AU - Liu, Chunyu
AU - Bandinelli, Stefania
AU - Boerwinkle, Eric
AU - Dehghan, Abbas
AU - Schwartz, Joel D.
AU - Psaty, Bruce M.
AU - Feinberg, Andrew P.
AU - Hou, Lifang
AU - Ferrucci, Luigi
AU - Sotoodehnia, Nona
AU - Matullo, Giuseppe
AU - Peters, Annette
AU - Fornage, Myriam
AU - Assimes, Themistocles L.
AU - Whitsel, Eric A.
AU - Levy, Daniel
AU - Baccarelli, Andrea A.
N1 - Copyright:
This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine
PY - 2019/8/20
Y1 - 2019/8/20
N2 - 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.
AB - 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.
KW - coronary artery disease
KW - coronary heart disease
KW - epigenetics
KW - gene expression regulation
KW - genomics
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U2 - 10.1161/CIRCULATIONAHA.118.039357
DO - 10.1161/CIRCULATIONAHA.118.039357
M3 - Article
C2 - 31424985
AN - SCOPUS:85071560527
VL - 140
SP - 645
EP - 657
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 8
ER -