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Original Investigation
June 2018

Association of Methylation Signals With Incident Coronary Heart Disease in an Epigenome-Wide Assessment of Circulating Tumor Necrosis Factor α

Author Affiliations
  • 1Department of Epidemiology, University of Alabama, Birmingham
  • 2The Robert N. Butler Columbia Aging Center, Columbia University Mailman School of Public Health, New York, New York
  • 3Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York
  • 4Now with Mount Sinai School of Medicine, New York, New York
  • 5Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
  • 6Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 7Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
  • 8Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom
  • 9Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany
  • 10German Center for Diabetes Research, Neuherberg, Germany
  • 11Framingham Heart Study, Framingham, Massachusetts
  • 12Boston University School of Medicine, Boston, Massachusetts
  • 13Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts
  • 14Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
  • 15Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
  • 16Medical Research Council–Public Health England Centre for Environment and Health and Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom
  • 17Hudson Alpha Institute for Biotechnology, Huntsville, Alabama
  • 18Institute of Genetic Epidemiology, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany
  • 19Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland
  • 20Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
  • 21Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, Massachusetts
  • 22Mathematical and Statistical Computing Laboratory, Center for Information Technology, Bethesda, Maryland
  • 23Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, Massachusetts
  • 24Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York
  • 25Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
  • 26Division of General Internal Medicine, Massachusetts General Hospital, Boston,
  • 27Department of Medicine, Harvard Medical School, Boston, Massachusetts
  • 28Program in Population and Medical Genetics, Broad Institute, Cambridge, Massachusetts
  • 29Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 30Longitudinal Study Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
  • 31Institute of Epidemiology, Helmholtz Zentrum München German Research Centre for Environmental Health, Neuherberg, Germany
  • 32Deutsches Zentrum fur Herz-Kreislauf-Forschung (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany
  • 33Institute of Human Genetics, Technical University Munich, Munich, Germany
  • 34Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany
  • 35Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University, Düsseldorf, Germany
  • 36Department of Endocrinology and Diabetology, Heinrich-Heine University, Düsseldorf, Germany
  • 37Institute for Clinical Diabetology, Düsseldorf, Germany
  • 38German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
  • 39Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
  • 40Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom
  • 41Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 42Veterans Affairs Normative Aging Study, VA Boston Healthcare System, Boston, Massachusetts
  • 43School of Biomedical Informatics, University of Texas Health Science Center, Houston
  • 44Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy
  • 45Alzheimer Scotland Dementia Research Centre, The University of Edinburgh, Edinburgh, United Kingdom
  • 46Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom
  • 47Department of Psychology, The University of Edinburgh, Edinburgh, United Kingdom
  • 48Department of General Practice and Primary Health Care, Faculty of Medicine, University of Helsinki, Helsinki, Finland
  • 49German Diabetes Center, Institute for Clinical Diabetology, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  • 50Center for Life-Course Health Research, Northern Finland Cohort Center, Finland and Biocenter Oulu, University of Oulu, Oulu, Finland
  • 51Unit of Primary Care, Oulu University Hospital, Oulu, Finland
  • 52College of Public Health, University of Kentucky, Lexington
JAMA Cardiol. 2018;3(6):463-472. doi:10.1001/jamacardio.2018.0510
Key Points

Question  Is DNA methylation in peripheral blood cells associated with circulating tumor necrosis factor α levels and risk of coronary heart disease?

Findings  In this epigenome-wide study, top methylation loci associated with circulating tumor necrosis factor α concentration in whole blood or CD4+ T cells were located in or near the DTX3L-PARP9 gene complex, NLRC5, and ABO. The findings in NLRC5 and DTX3L-PARP9 were successfully replicated and linked to gene expression, and methylation at these loci was robustly inversely associated with the risk of incident coronary heart disease.

Meaning  After further validation, these epigenetic associations might be useful in the pursuit of new or improved therapeutic applications.

Abstract

Importance  Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine with manifold consequences for mammalian pathophysiology, including cardiovascular disease. A deeper understanding of TNF-α biology may enhance treatment precision.

Objective  To conduct an epigenome-wide analysis of blood-derived DNA methylation and TNF-α levels and to assess the clinical relevance of findings.

Design, Setting, and Participants  This meta-analysis assessed epigenome-wide associations in circulating TNF-α concentrations from 5 cohort studies and 1 interventional trial, with replication in 3 additional cohort studies. Follow-up analyses investigated associations of identified methylation loci with gene expression and incident coronary heart disease; this meta-analysis included 11 461 participants who experienced 1895 coronary events.

Exposures  Circulating TNF-α concentration.

Main Outcomes and Measures  DNA methylation at approximately 450 000 loci, neighboring DNA sequence variation, gene expression, and incident coronary heart disease.

Results  The discovery cohort included 4794 participants, and the replication study included 816 participants (overall mean [SD] age, 60.7 [8.5] years). In the discovery stage, circulating TNF-α levels were associated with methylation of 7 cytosine-phosphate-guanine (CpG) sites, 3 of which were located in or near DTX3L-PARP9 at cg00959259 (β [SE] = −0.01 [0.003]; P = 7.36 × 10−8), cg08122652 (β [SE] = −0.008 [0.002]; P = 2.24 × 10−7), and cg22930808(β [SE] = −0.01 [0.002]; P = 6.92 × 10−8); NLRC5 at cg16411857 (β [SE] = −0.01 [0.002]; P = 2.14 × 10−13) and cg07839457 (β [SE] = −0.02 [0.003]; P = 6.31 × 10−10); or ABO, at cg13683939 (β [SE] = 0.04 [0.008]; P = 1.42 × 10−7) and cg24267699 (β [SE] = −0.009 [0.002]; P = 1.67 × 10−7), after accounting for multiple testing. Of these, negative associations between TNF-α concentration and methylation of 2 loci in NLRC5 and 1 in DTX3L-14 PARP9 were replicated. Replicated TNF-α–linked CpG sites were associated with 9% to 19% decreased risk of incident coronary heart disease per 10% higher methylation per CpG site (cg16411857: hazard ratio [HR], 0.86; 95% CI, 0.78-1.95; P = .003; cg07839457: HR, 0.89; 95% CI, 0.80-0.94; P = 3.1 × 10−5; cg00959259: HR, 0.91; 95% CI, 0.84-0.97; P = .002; cg08122652: HR, 0.81; 95% CI, 0.74-0.89; P = 2.0 × 10−5).

Conclusions and Relevance  We identified and replicated novel epigenetic correlates of circulating TNF-α concentration in blood samples and linked these loci to coronary heart disease risk, opening opportunities for validation and therapeutic applications.

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