TY - JOUR
T1 - Association of methylation signals with incident coronary heart disease in an epigenome-wide assessment of circulating tumor necrosis factor
AU - Aslibekyan, Stella
AU - Agha, Golareh
AU - Colicino, Elena
AU - Do, Anh N.
AU - Lahti, Jari
AU - Ligthart, Symen
AU - Marioni, Riccardo E.
AU - Marzi, Carola
AU - Mendelson, Michael M.
AU - Tanaka, Toshiko
AU - Wielscher, Matthias
AU - Absher, Devin M.
AU - Ferrucci, Luigi
AU - Franco, Oscar H.
AU - Gieger, Christian
AU - Grallert, Harald
AU - Hernandez, Dena
AU - Huan, Tianxiao
AU - Iurato, Stella
AU - Joehanes, Roby
AU - Just, Allan C.
AU - Kunze, Sonja
AU - Lin, Honghuang
AU - Liu, Chunyu
AU - Meigs, James B.
AU - Van Meurs, Joyce B.J.
AU - Moore, Ann Zenobia
AU - Peters, Annette
AU - Prokisch, Holger
AU - Raikkonen, Katri
AU - Rathmann, Wolfgang
AU - Roden, Michael
AU - Schramm, Katharina
AU - Schwartz, Joel D.
AU - Starr, John M.
AU - Uitterlinden, Andre G.
AU - Vokonas, Pantel
AU - Waldenberger, Melanie
AU - Yao, Chen
AU - Zhi, Degui
AU - Baccarelli, Andrea A.
AU - Bandinelli, Stefania
AU - Deary, Ian J.
AU - Dehghan, Abbas
AU - Eriksson, Johan
AU - Herder, Christian
AU - Jarvelin, Marjo Riitta
AU - Levy, Daniel
AU - Arnett, Donna K.
N1 - Publisher Copyright:
© 2018 American Medical Association. All rights reserved.
PY - 2018/6
Y1 - 2018/6
N2 - 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.
AB - 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.
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U2 - 10.1001/jamacardio.2018.0510
DO - 10.1001/jamacardio.2018.0510
M3 - Article
C2 - 29617535
AN - SCOPUS:85048714326
SN - 2380-6583
VL - 3
SP - 463
EP - 472
JO - JAMA Cardiology
JF - JAMA Cardiology
IS - 6
ER -