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

Stella Aslibekyan, Golareh Agha, Elena Colicino, Anh N. Do, Jari Lahti, Symen Ligthart, Riccardo E. Marioni, Carola Marzi, Michael M. Mendelson, Toshiko Tanaka, Matthias Wielscher, Devin M. Absher, Luigi Ferrucci, Oscar H. Franco, Christian Gieger, Harald Grallert, Dena Hernandez, Tianxiao Huan, Stella Iurato, Roby JoehanesAllan C. Just, Sonja Kunze, Honghuang Lin, Chunyu Liu, James B. Meigs, Joyce B.J. Van Meurs, Ann Zenobia Moore, Annette Peters, Holger Prokisch, Katri Raikkonen, Wolfgang Rathmann, Michael Roden, Katharina Schramm, Joel D. Schwartz, John M. Starr, Andre G. Uitterlinden, Pantel Vokonas, Melanie Waldenberger, Chen Yao, Degui Zhi, Andrea A. Baccarelli, Stefania Bandinelli, Ian J. Deary, Abbas Dehghan, Johan Eriksson, Christian Herder, Marjo Riitta Jarvelin, Daniel Levy, Donna K. Arnett

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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 biologymay 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.

Original languageEnglish
Pages (from-to)463-472
Number of pages10
JournalJAMA Cardiology
Issue number6
StatePublished - Jun 2018

Bibliographical note

Funding Information:
Funding/Support: The Framingham Heart Study is funded by the National Institutes of Health (NIH) (grants N01-HC-25195 and HHSN268201500001I) and administered by Boston University; the DNA methylation and gene expression assays for this investigation were funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI) of the NIH, and an NIH Director’s Challenge Award (Dr Levy), while the analytic component of this project was funded by the Division of Intramural Research, NHLBI, and the Center for Information Technology at the NIH. This study also used the computational resources of the Biowulf system at the NIH ( and additional partial support from the Tommy Kaplan Fund, Boston Children’s Hospital, and NIH NHLBI (grant K99 HL136875) (Dr Mendelson) and the National Institute of Diabetes and Digestive and Kidney Diseases (grants K24 DK080140 and U01 DK078616; Dr Meigs); the TNF-α assay was supported by a Career Development Award from the American Diabetes Association (Dr Meigs). The Genetics of Lipid-Lowering Drugs and Diet Network project was funded by NIH NHLBI (grant R01 HL104135, Dr Arnett), and this analysis was enabled by NIH NHLBI (grant K01 136700, Dr Aslibekyan). The Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland (grants 1284859 and 12848591), the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, the Signe and Ane Gyllenberg Foundation, University of Helsinki, Finnish Ministry of Education, Ahokas Foundation, and the Emil Aaltonen Foundation. The Invecchiare in Chianti baseline study (1998-2000) was supported as a targeted project of the Italian Ministry of Health (grant ICS110.1/RF97.71) and the US National Institute on Aging (grants 263 MD 9164 and 263 MD 821336). The Kooperative Gesundheitsforschung in der Region Augsburg (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 and by the State of Bavaria. The KORA research was also supported by the Munich Center of Health Sciences and by Ludwig-Maximilians-Universität as part of LMUinnovativ, and the research leading to these results has received funding from the European Union Seventh Framework Programme (grants 261433 [BioSHaRe] and 603288 [sysVASC]). Study center the German Diabetes Center is funded by the German Federal Ministry of Health and the Ministry of Innovation, Science, Research and Technology of the State North Rhine-Westphalia, and this study was supported in part by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research. The Lothian Birth Cohort 1921 phenotype collection was supported by the UK Biotechnology and Biological Sciences Research Council, 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. Partial support was received from the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (Drs Marioni, Starr, and Deary), which is supported by funding from the Biotechnology and Biological Sciences Research Council, the Economic and Social Research Council, the Medical Research Council, and the University of Edinburgh as part of the cross-council Lifelong Health and Wellbeing initiative (MR/K026992/1). The US Department of Veterans Affairs (VA) Normative Aging Study is supported by grants from the National Institute of Environmental Health Sciences (NIEHS) (grants R01ES021733, R01ES025225-01A1, ES015172, ES014663, and ES020010) and Environmental Protection Agency (grant RD832416), the Cooperative Studies Program/ERIC, and US Department of Veterans Affairs and is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC); additional support was provided by the US Department of Agriculture Agricultural Research Service (grant 53-K06-510). With respect to the Northern Finland Birth Cohort 1966, the present analysis was supported by the European Union Horizon 2020 research and innovation programme (grant 633212, Dr Wielscher). The Northern Finland Birth Cohort 1966 cohort received financial support from the Academy of Finland (grants 104781, 120315, 129269, 1114194, and 24300796) the Center of Excellence in Complex Disease Genetics and SALVE, University Hospital Oulu, Biocenter, University of Oulu, Finland (grant 75617), NHLBI (grant R01 HL087679) through the STAMPEED program (grant R01 MH083268), NIH National Institute of Mental Health (grant R01 MH63706), the ENGAGE project, and grant HEALTH-F4-2007-201413, EU FP7 EurHEALTHAgeing-277849, the Medical Research Council UK (grants G0500539, G0600705, G1002319, PrevMetSyn/SALVE) and the MRC Centenary Early Career Award; the program is currently being funded by grant H2020-633595 DynaHEALTH action, academy of Finland EGEA-project (285547) and EU H2020 ALEC project (grant 633212). The Rotterdam Study generation and management of the methylation array data was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands; methylation data were funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus University Medical Center; and by the Netherlands Organization for Scientific Research (grant 184021007). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University Medical Center, Rotterdam; Netherlands Organization for the Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission; and the Municipality of Rotterdam.

Funding Information:
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.

Publisher Copyright:
© 2018 American Medical Association. All rights reserved.

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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