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; TianXiao 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 Hernandez; Luke 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

doi:10.1161/CIRCULATIONAHA.118.039357

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

Circulation. 2019 Aug 20;140(8):645-657. doi: 10.1161/CIRCULATIONAHA.118.039357. Epub 2019 Aug 19.

Authors

Golareh Agha¹, Michael M Mendelson^{2

3

4}, Cavin K Ward-Caviness^{5

6}, Roby Joehanes^{2

7}, TianXiao Huan⁸, Rahul Gondalia⁹, Elias Salfati¹⁰, Jennifer A Brody¹¹, Giovanni Fiorito¹², Jan Bressler¹³, Brian H Chen¹⁴, Symen Ligthart¹⁵, Simonetta Guarrera¹², Elena Colicino¹⁶, Allan C Just¹⁶, Simone Wahl¹⁷, Christian Gieger¹⁷, Amy R Vandiver¹⁸, Toshiko Tanaka¹⁴, Dena G Hernandez¹⁹, Luke C Pilling²⁰, Andrew B Singleton¹⁹, Carlotta Sacerdote²¹, Vittorio Krogh²², Salvatore Panico²³, Rosario Tumino²⁴, Yun Li²⁵, Guosheng Zhang²⁶, James D Stewart²⁷, James S Floyd¹¹, Kerri L Wiggins¹¹, Jerome I Rotter²⁸, Michael Multhaup¹⁸, Kelly Bakulski²⁹, Steven Horvath³⁰, Philip S Tsao¹⁰, Devin M Absher³¹, Pantel Vokonas³², Joel Hirschhorn^{33

34}, M Daniele Fallin³⁵, Chunyu Liu³⁶, Stefania Bandinelli³⁷, Eric Boerwinkle^{38

39}, Abbas Dehghan⁴⁰, Joel D Schwartz⁴¹, Bruce M Psaty^{42

43}, Andrew P Feinberg⁴⁴, Lifang Hou⁴⁵, Luigi Ferrucci⁴⁶, Nona Sotoodehnia⁴⁷, Giuseppe Matullo¹², Annette Peters^{48

49}, Myriam Fornage⁵⁰, Themistocles L Assimes⁵¹, Eric A Whitsel⁵², Daniel Levy^{2

3}, Andrea A Baccarelli¹

Affiliations

¹ Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York (G.A., A.A.B.).
² Population Sciences Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD (M.M.M., D.L., R.J.).
³ Framingham Heart Study, MA (M.M.M., D.L.).
⁴ Department of Cardiology, Boston Children's Hospital, MA (M.M.M.).
⁵ National Health and Environmental Effects Research Laboratory, Environmental Public Health Division, Chapel Hill, NC (C.K.W.C.).
⁶ Institute of Epidemiology II, Helmholtz Institute, Ingolstaedter Landstrasse 1, Neuherberg, Germany (C.K.W.C.).
⁷ Hebrew SeniorLife, Harvard Medical School, Boston, MA (R.J.).
⁸ The Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD (T.X.H.).
⁹ Department of Epidemiology (R.G.), University of North Carolina, Chapel Hill.
¹⁰ Department of Medicine, Stanford University School of Medicine, CA (E.S., P.S.T.).
¹¹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle (J.A.B., J.S.F., K.L.W.).
¹² Italian Institute for Genomic Medicine (IIGM/HuGeF) and Department of Medical Sciences, University of Turin, Italy (G.F., S.G., G.M.).
¹³ Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston (J.B.).
¹⁴ Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD (B.H.C., T.T.).
¹⁵ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands (S.L.).
¹⁶ Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY (E.C., A.C.J.).
¹⁷ Research Unit Molecualr Epidemiology, Helmholtz Zentrum München, Germany (S.W., C.G.).
¹⁸ Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD (A.R.V., M.M.).
¹⁹ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD (D.G.H., A.B.S.).
²⁰ Epidemiology and Public Health Group, University of Exeter Medical School, United Kingdom (L.C.P.).
²¹ Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy (C.S.).
²² Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (V.K.).
²³ Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy (S.P.).
²⁴ Cancer Registry And Histopathology Department, Civic- M.P. Arezzo2 Hospital, Asp Ragusa, Italy (R.T.).
²⁵ Department of Genetics, Department of Biostatistics, Department of Computer Science (Y.L.), University of North Carolina, Chapel Hill.
²⁶ Curriculum in Bioinformatics and Computational Biology, Department of Genetics, and Department of Statistics (G.Z.), University of North Carolina, Chapel Hill.
²⁷ Carolina Population Center and Department of Epidemiology (J.D.S.), University of North Carolina, Chapel Hill.
²⁸ The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA (J.I.R.).
²⁹ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor (K.B.).
³⁰ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles (S.H.).
³¹ HudsonAlpha institute of Biotechnology, Huntsville, AL (D.M.A.).
³² VA Normative Aging Study, VA Boston Healthcare System, Department of Medicine, Boston University School of Medicine, MA (P.V.).
³³ Department of Medicine, Division of Endocrinology, Boston Children's Hospital, MA (J.H.).
³⁴ Departments of Medicine and Pediatrics, Harvard Medical School, Boston, MA (J.H.).
³⁵ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (M.D.F.).
³⁶ Department of Biostatistics, Boston University School of Public Health, MA (C.L.).
³⁷ Azienda Sanitaria, USL Centro Firenze, Italy (S.B.).
³⁸ Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston (E.B.).
³⁹ Human Genome Sequencing Center, Baylor College of Medicine, TX (E.B.).
⁴⁰ Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of 346 Public Health, Imperial College London, United Kingdom (A.D.).
⁴¹ Department of Epidemiology and Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA (J.D.S.).
⁴² Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle (B.M.P.).
⁴³ Kaiser Permanente Washington Health Research Institute, Seattle (B.M.P.).
⁴⁴ Departments of Medicine, Biomedical Engineering, and Mental Health, Johns Hopkins University, Baltimore, MD (A.P.F.).
⁴⁵ Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center and Department of Preventive Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL (L.H.).
⁴⁶ Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD (L.F.).
⁴⁷ Division of Cardiology, Departments of Medicine and Epidemiology, Cardiovascular Health Research Unit, University of Washington, Seattle (N.S.).
⁴⁸ Helmholtz Zentrum München, Institute of Epidemiology, Neuherberg, Germany; German Research Center for Cardiovascular Disease (DzHK e.V. - partner site Munich), Germany (A.P.).
⁴⁹ Ludwig-Maximilians University, Institute for Biometry, Medical Information Science and Epidemiology, Munich, Germany (A.P.).
⁵⁰ Brown Foundation Institute of Molecular Medicine McGovern Medical School, and Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston (M.F.).
⁵¹ Department of Medicine (Cardiovascular Medicine), and Department of Health Research & Policy, Stanford University School of Medicine, CA (T.L.A.).
⁵² Department of Epidemiology, Gillings School of Global Public Health, and Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill (E.A.W.).

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.

Keywords: coronary artery disease; coronary heart disease; epigenetics; gene expression regulation; genomics.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Aged
Cohort Studies
Coronary Disease / diagnosis*
Coronary Disease / epidemiology
CpG Islands / genetics*
DNA Methylation / physiology*
Europe / epidemiology
Female
Genome-Wide Association Study
Humans
Incidence
Leukocytes / physiology*
Male
Middle Aged
Myocardial Infarction / diagnosis*
Myocardial Infarction / epidemiology
Population Groups
Prognosis
Prospective Studies
Risk
United States / epidemiology

Abstract

Publication types

MeSH terms

Grants and funding