Meta-Analysis

. 2018 Jun 1;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

Stella Aslibekyan¹, Golareh Agha², Elena Colicino³, Anh N Do^{1

4}, Jari Lahti⁵, Symen Ligthart⁶, Riccardo E Marioni^{7

8}, Carola Marzi^{9

10}, Michael M Mendelson^{11

12

13

14}, Toshiko Tanaka¹⁵, Matthias Wielscher¹⁶, Devin M Absher¹⁷, Luigi Ferrucci¹⁵, Oscar H Franco⁶, Christian Gieger^{9

10

18}, Harald Grallert^{9

10}, Dena Hernandez¹⁹, Tianxiao Huan^{11

14}, Stella Iurato²⁰, Roby Joehanes^{21

22

23}, Allan C Just²⁴, Sonja Kunze^{9

10}, Honghuang Lin²⁵, Chunyu Liu^{11

14}, James B Meigs^{26

27

28}, Joyce B J van Meurs²⁹, Ann Zenobia Moore³⁰, Annette Peters^{16

31

32}, Holger Prokisch^{33

34}, Katri Räikkönen⁵, Wolfgang Rathmann³⁵, Michael Roden^{36

37

38}, Katharina Schramm^{33

34}, Joel D Schwartz³⁹, John M Starr^{40

41}, André G Uitterlinden^{6

29}, Pantel Vokonas⁴², Melanie Waldenberger^{9

10}, Chen Yao^{11

14}, Degui Zhi⁴³, Andrea A Baccarelli³, Stefania Bandinelli⁴⁴, Ian J Deary^{41

40

45}, Abbas Dehghan¹⁶, Johan Eriksson⁴⁶, Christian Herder^{10

47}, Marjo-Riitta Jarvelin^{16

48

49}, Daniel Levy^{11

14}, Donna K Arnett⁵⁰

Affiliations

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

PMID: 29617535
PMCID: PMC6100733
DOI: 10.1001/jamacardio.2018.0510

Meta-Analysis

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

Stella Aslibekyan et al. JAMA Cardiol. 2018.

. 2018 Jun 1;3(6):463-472.

doi: 10.1001/jamacardio.2018.0510.

Authors

Affiliations

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

PMID: 29617535
PMCID: PMC6100733
DOI: 10.1001/jamacardio.2018.0510

Erratum in

Error in End Matter.
[No authors listed] [No authors listed] JAMA Cardiol. 2018 Jun 1;3(6):505. doi: 10.1001/jamacardio.2018.1429. JAMA Cardiol. 2018. PMID: 29799969 Free PMC article. No abstract available.

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Aslibekyan reports grants from the National Institutes of Health (National Heart, Lung, and Blood Institute). Dr Deary reports grants from Age UK and the Medical Research Council. Dr Dehghan reports grants and personal fees from Metagenics Inc. Dr Do received consultancy and research support from Metagenics Inc. Dr Franco reports receiving personal fees from ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd), Metagenics Inc, and AXA. Dr Herder reports personal fees from Sanofi Deutschland and Eli Lilly. Dr Schwartz reports grants from the National Institutes of Health. No other disclosures were reported.

Figures

See this image and copyright information in PMC

References

1. Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol. 2016;12(1):49-62. - PMC - PubMed
1. Brenner D, Blaser H, Mak TW. Regulation of tumour necrosis factor signalling: live or let die. Nat Rev Immunol. 2015;15(6):362-374. - PubMed
1. Pope JE. Rheumatoid arthritis: TNF inhibitors and cardiovascular risk management in RA. Nat Rev Rheumatol. 2016;12(6):317-318. - PubMed
1. Graf J. Study of adalimumab to lower cardiovascular risk in RA patients with well controlled joint disease. https://clinicaltrials.gov/ct2/show/NCT01893996. Published May 2, 2017. Accessed February 26, 2018.
1. Ridker PM, Everett BM, Thuren T, et al. ; CANTOS Trial Group . Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-1131. - PubMed

Publication types

Actions
Actions
Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources