Journal
JAMA CARDIOLOGY
Volume 3, Issue 6, Pages 463-472Publisher
AMER MEDICAL ASSOC
DOI: 10.1001/jamacardio.2018.0510
Keywords
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Categories
Funding
- National Institutes of Health (NIH) [N01-HC-25195, HHSN268201500001I]
- Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI) of the NIH
- NIH Director's Challenge Award
- Division of Intramural Research, NHLBI, and the Center for Information Technology at the NIH
- Tommy Kaplan Fund
- Boston Children's Hospital
- NIH NHLBI [K99 HL136875, R01 HL104135, K01 136700]
- National Institute of Diabetes and Digestive and Kidney Diseases [K24 DK080140, U01 DK078616]
- American Diabetes Association
- Academy of Finland [1284859, 12848591, 104781, 120315, 129269, 1114194, 24300796]
- Finnish Diabetes Research Society
- Folkhalsan Research Foundation
- Novo Nordisk Foundation
- Finska Lakaresallskapet
- Signe and Ane Gyllenberg Foundation
- University of Helsinki
- Finnish Ministry of Education
- Ahokas Foundation
- Emil Aaltonen Foundation
- Italian Ministry of Health [ICS110.1/RF97.71]
- US National Institute on Aging [263MD 9164, 263 MD 821336]
- Helmholtz Zentrum Munchen German Research Center for Environmental Health
- German Federal Ministry of Education and Research
- State of Bavaria
- Munich Center of Health Sciences
- Ludwig-Maximilians-Universitat as part of LMUinnovativ
- European Union Seventh Framework Programme [261433, 603288]
- German Federal Ministry of Health
- Ministry of Innovation, Science, Research and Technology of the State North Rhine-Westphalia
- UK Biotechnology and Biological Sciences Research Council
- Royal Society
- Chief Scientist Office of the Scottish Government
- Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK
- Wellcome Trust Institutional Strategic Support Fund
- University of Edinburgh
- University of Queensland
- University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology from the Biotechnology and Biological Sciences Research Council
- Economic and Social Research Council
- Medical Research Council
- University of Edinburgh as part of the cross-council Lifelong Health and Well being initiative [MR/K026992/1]
- National Institute of Environmental Health Sciences (NIEHS) [R01ES021733, R01ES025225-01A1, ES015172, ES014663, ES020010]
- Environmental Protection Agency [RD832416]
- Cooperative Studies Program/ERIC
- US Department of Veterans Affairs
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC)
- US Department of Agriculture Agricultural Research Service [53-K06-510]
- European Union Horizon 2020 research and innovation programme [633212]
- Center of Excellence in Complex Disease Genetics
- SALVE
- University Hospital Oulu
- Biocenter, University of Oulu, Finland [75617]
- NHLBI through the STAMPEED program [R01 HL087679, R01 MH083268]
- NIH National Institute of Mental Health [R01 MH63706]
- ENGAGE project
- EU FP7 EurHEALTHAgeing [277849]
- Medical Research Council UK [G0500539, G0600705, G1002319]
- MRC Centenary Early Career Award
- academy of Finland EGEA-project [285547]
- EU H2020 ALEC project [633212]
- Genetic Laboratory of the Department of Internal Medicine, Erasmus University Medical Center
- Netherlands Organization for Scientific Research [184021007]
- Erasmus Medical Center
- Erasmus University Medical Center, Rotterdam
- Netherlands Organization for the Health Research and Development
- Research Institute for Diseases in the Elderly
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission
- Municipality of Rotterdam
- [HEALTH-F4-2007-201413]
- [H2020-633595]
- BBSRC [BB/F019394/1] Funding Source: UKRI
- MRC [G1002319, G0600705] Funding Source: UKRI
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IMPORTANCE Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine with manifold consequences for mammalian pathophysiology, including cardiovascular disease. A deeper understanding of TNF-alpha biology may enhance treatment precision. OBJECTIVE To conduct an epigenome-wide analysis of blood-derived DNA methylation and TNF-alpha levels and to assess the clinical relevance of findings. DESIGN, SETTING, AND PARTICIPANTS This meta-analysis assessed epigenome-wide associations in circulating TNF-alpha 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 11461 participants who experienced 1895 coronary events. EXPOSURES Circulating TNF-alpha 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-alpha levels were associated with methylation of 7 cytosine-phosphate-guanine (CpG) sites, 3 of which were located in or near DTX3L-PARP9 at cg00959259 (beta[SE] = -0.01 [0.003]; P = 7.36 x 10(-8)), cg08122652 (beta[SE] = -0.008 [0.002]; P = 2.24 x 10 -7 ), and cg22930808(beta[SE] = -0.01 [0.002]; P = 6.92 x 10(-8)); NLRC5 at cg16411857 (beta[SE] = -0.01 [0.002]; P = 2.14 x 10(-13)) and cg07839457 (beta[SE] = -0.02 [0.003]; P = 631 x 10(-10)); or ABO, at cg13683939 (beta[SE] = 0.04 [0.008]; P = 1.42 x 10(-7)) and cg24267699 (beta[SE] = -0.009 [0.002]; P = 1.67 x 10(-7)), after accounting for multiple testing. Of these, negative associations between TNF-alpha concentration and methylation of 2 loci in NLRC5 and 1 in DTX3L-14 PARP9 were replicated. Replicated TNF-alpha-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% Cl. 0.78-1.95; P = .003; cg07839457: HR, 0.89; 95% CI, 0.80-0.94; P = 3.1 x 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 x 10(-5)). CONCLUSIONS AND RELEVANCE We identified and replicated novel epigenetic correlates of circulating TNF-alpha concentration in blood samples and linked these loci to coronary heart disease risk, opening opportunities for validation and therapeutic applications.
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