Association of methylation signals with incident coronary heart disease in an epigenome-wide assessment of circulating tumor necrosis factor α
Aslibekyan, Stella; Agha, Golareh; Colicino, Elena; Do, Anh N.; Lahti, Jari; Ligthart, Symen; Marioni, Riccardo E.; Marzi, Carola; Mendelson, Michael M.; Tanaka, Toshiko; Wielscher, Matthias; Absher, Devin M.; Ferrucci, Luigi; Franco, Oscar H.; Gieger, Christian; Grallert, Harald; Hernandez, Dena; Huan, Tianxiao; Iurato, Stella; Joehanes, Roby; Just, Allan C.; Kunze, Sonja; Lin, Honghuang; Liu, Chunyu; Meigs, James B.; van Meurs, Joyce B.J.; Moore, Ann Zenobia; Peters, Annette; Prokisch, Holger; Räikkönen, Katri; Rathmann, Wolfgang; Roden, Michael; Schramm, Katharina; Schwartz, Joel D.; Starr, John M.; Uitterlinden, André G.; Vokonas, Pantel; Waldenberger, Melanie; Yao, Chen; Zhi, Degui; Baccarelli, Andrea A.; Bandinelli, Stefania; Deary, Ian J.; Dehghan, Abbas; Eriksson, Johan; Herder, Christian; Järvelin, Marjo-Riitta; Levy, Daniel; Arnett, Donna K. (2018-06-30)
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
© 2018, American Medical Association. The final authenticated version is available online at https://doi.org/10.1001/jamacardio.2018.0510.
https://rightsstatements.org/vocab/InC/1.0/
https://urn.fi/URN:NBN:fi-fe2019052717369
Tiivistelmä
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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