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

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.).

PMID: 31424985
PMCID: PMC6812683
DOI: 10.1161/CIRCULATIONAHA.118.039357

Meta-Analysis

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

Golareh Agha et al. Circulation. 2019.

. 2019 Aug 20;140(8):645-657.

doi: 10.1161/CIRCULATIONAHA.118.039357. Epub 2019 Aug 19.

Authors

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.).

PMID: 31424985
PMCID: PMC6812683
DOI: 10.1161/CIRCULATIONAHA.118.039357

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.

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Figures

**Figure 1.**
Overall analytic workflow. *Af. Am.* denotes individuals of African-American ancestry; *Eur* denotes individuals of European ancestry. meQTLs: methylation quantitative trait loci.

**Figure 2.**
Plot of effect sizes (i.e., log hazard ratios) and 95% confidence intervals (CIs) for the 52 coronary heart disease (CHD)-associated CpG DNA methylation sites, comparing results from the incident CHD meta-analysis (blue) vs the incident MI-only meta-analysis (orange).

**Figure 3.**
Adapted UCSC genome browser image - for genomic location of CpGs cg07289306 and cg26470101. The red zoom-in triangles are our addition to the UCSC image (http://genome.ucsc.edu), and represent a magnified region corresponding to the red marked region on each chromosome. The yellow highlights are also our addition, and highlight the exact genomic location of each CpG

See this image and copyright information in PMC

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

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

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