University of Oulu

Aslibekyan S, Agha G, Colicino E, et al. Association of Methylation Signals With Incident Coronary Heart Disease in an Epigenome-Wide Assessment of Circulating Tumor Necrosis Factor α. JAMA Cardiol. 2018;3(6):463–472. doi:10.1001/jamacardio.2018.0510

Association of methylation signals with incident coronary heart disease in an epigenome-wide assessment of circulating tumor necrosis factor α

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Author: Aslibekyan, Stella1; Agha, Golareh2; Colicino, Elena3;
Organizations: 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
41Alzheimer Scotland Dementia Research Centre, The University of Edinburgh, Edinburgh, United Kingdom
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
45Department of Psychology, The University of Edinburgh, Edinburgh, United Kingdom
46Department of General Practice and Primary Health Care, Faculty of Medicine, University of Helsinki, Helsinki, Finland
47German Diabetes Center, Institute for Clinical Diabetology, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
48Center for Life-Course Health Research, Northern Finland Cohort Center, Finland and Biocenter Oulu, University of Oulu, Oulu, Finland
49Unit of Primary Care, Oulu University Hospital, Oulu, Finland
50College of Public Health, University of Kentucky, Lexington
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 2.7 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2019052717369
Language: English
Published: American Medical Association, 2018
Publish Date: 2019-06-30
Description:

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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Series: JAMA cardiology
ISSN: 2380-6583
ISSN-E: 2380-6591
ISSN-L: 2380-6583
Volume: 3
Issue: 6
Pages: 463 - 472
DOI: 10.1001/jamacardio.2018.0510
OADOI: https://oadoi.org/10.1001/jamacardio.2018.0510
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Subjects:
Funding: The participating studies acknowledge the following sources of funding: FHS: The Framingham Heart Study is funded by National Institutes of Health (NIH) contract N01-HC-25195 and HHSN268201500001I and administered by Boston University. The DNA methylation and gene expression assays for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI), NIH, and an NIH Director’s Challenge Award (Levy). The analytic component of this project was funded by the Division of Intramural Research, NHLBI, and the Center for Information Technology, NIH, Bethesda, MD. This study used the computational resources of the Biowulf system at the NIH, Bethesda, MD (https://hpc.nih.gov/). Dr. Mendelson was partly supported by the Tommy Kaplan Fund, Boston Children’s Hospital and the NIH NHLBI K99 HL136875. The TNFα assay was supported by a Career Development Award from the American Diabetes Association (Meigs). Dr. Meigs is supported by NIDDK K24 DK080140 and U01 DK078616. GOLDN: The GOLDN project was funded by NIH NHLBI R01 HL104135 (Arnett) and this analysis was enabled by NIH NHLBI K01 136700 (Aslibekyan). 29 HBCS: The Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland (1284859 and 12848591), the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation. InCHIANTI: The InCHIANTI study baseline (1998-2000) was supported as a "targeted project" (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336). KORA: The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreements # 261433 (BioSHaRe) and # 603288 (sysVASC). The German Diabetes Center is funded by the German Federal Ministry of Health (BMG) and the Ministry of Innovation, Science, Research and Technology (MIWF) of the State North Rhine-Westphalia. This study was supported in part by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.) 30 LBC1921: Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Methylation typing was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. REM, JMS, and IJD are members of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE). CCACE is supported by funding from the BBSRC, the Economic and Social Research Council (ESRC), the Medical Research Council (MRC), and the University of Edinburgh as part of the cross-council Lifelong Health and Wellbeing initiative (MR/K026992/1). NAS: This study is supported by grants from the National Institute of Environmental Health Sciences (NIEHS) (R01ES021733, R01ES025225-01A1, ES015172, ES014663 and ES020010) and Environmental Protection Agency (EPA) grant RD832416. The US Department of Veterans Affairs (VA) Normative Aging Study (NAS) is supported by the Cooperative Studies Program/ERIC, US Department of Veterans Affairs, and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). The views expressed in this paper are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs. Additional support was provided by the US Department of Agriculture, Agricultural Research Service (contract 53-K06-510). NFBC66: The present analysis was supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement #633212 (Wielscher). NFBC1966 received financial support from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, 24300796, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), NHLBI grant R01 HL087679 through the STAMPEED program (R01 MH083268), NIH/NIMH (R01 MH63706), ENGAGE project and grant agreement HEALTH-F4-2007-201413, EU FP7 EurHEALTHAgeing-277849, the Medical Research Council, UK (G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and the MRC, Centenary Early Career Award. The program is currently being funded by the H2020-633595 DynaHEALTH action, academy of Finland EGEA-project (285547) and EU H2020 ALEC project (Grant Agreement 633212). RS: The generation and management of the methylation array data for the Rotterdam Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. The methylation data were funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by the Netherlands Organization for Scientific Research (NWO; project number 184021007). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam.
EU Grant Number: (633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
(277849) EURHEALTHAGEING - European ResearcH on DevElopmentAL, BirtH and Genetic Determinants of Ageing
Academy of Finland Grant Number: 285547
Detailed Information: 285547 (Academy of Finland Funding decision)
Copyright information: © 2018, American Medical Association. The final authenticated version is available online at https://doi.org/10.1001/jamacardio.2018.0510.