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

Department of Epidemiology, University of Alabama, Birmingham. The Robert N. Butler Columbia Aging Center, Columbia University Mailman School of Public Health, New York, New York. Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, New York. Now with Mount Sinai School of Medicine, New York, New York. Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom. Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom. Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany. German Center for Diabetes Research, Neuherberg, Germany. Framingham Heart Study, Framingham, Massachusetts. Boston University School of Medicine, Boston, Massachusetts. Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts. Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland. Medical Research Council-Public Health England Centre for Environment and Health and Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom. Hudson Alpha Institute for Biotechnology, Huntsville, Alabama. Institute of Genetic Epidemiology, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany. Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland. Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany. Division of Intramural Research, National Heart, Lung and Blood Institute, Framingham, Massachusetts. Mathematical and Statistical Computing Laboratory, Center for Information Technology, Bethesda, Maryland. Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, Massachusetts. Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, New York. Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts. Division of General Internal Medicine, Massachusetts General Hospital, Boston. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Program in Population and Medical Genetics, Broad Institute, Cambridge, Massachusetts. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands. Longitudinal Study Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland. Institute of Epidemiology, Helmholtz Zentrum München German Research Centre for Environmental Health, Neuherberg, Germany. Deutsches Zentrum fur Herz-Kreislauf-Forschung (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany. Institute of Human Genetics, Technical University Munich, Munich, Germany. Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany. Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University, Düsseldorf, Germany. Department of Endocrinology and Diabetology, Heinrich-Heine University, Düsseldorf, Germany. Institute for Clinical Diabetology, Düsseldorf, Germany. German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom. Alzheimer Scotland Dementia Research Centre, The University of Edinburgh, Edinburgh, United Kingdom. Veterans Affairs Normative Aging Study, VA Boston Healthcare System, Boston, Massachusetts. School of Biomedical Informatics, University of Texas Health Science Center, Houston. Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy. Department of Psychology, The University of Edinburgh, Edinburgh, United Kingdom. Department of General Practice and Primary Health Care, Faculty of Medicine, University of Helsinki, Helsinki, Finland. German Diabetes Center, Institute for Clinical Diabetology, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany. Center for Life-Course Health Research, Northern Finland Cohort Center, Finland and Biocenter Oulu, University of Oulu, Oulu, Finland. Unit of Primary Care, Oulu University Hospital, Oulu, Finland. College of Public Health, University of Kentucky, Lexington.

JAMA cardiology. 2018;(6):463-472
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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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Publication Type : Meta-Analysis

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