TY - JOUR
T1 - Association of methylation signals with incident coronary heart disease in an epigenome-wide assessment of circulating tumor necrosis factor α
AU - Aslibekyan, Stella
AU - Agha, Golareh
AU - Colicino, Elena
AU - Do, Anh N.
AU - Lahti, Jari
AU - Ligthart, Symen
AU - Marioni, Riccardo
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 - vVan Meurs, Joyce B. J.
AU - Moore, Ann Zenobia
AU - Peters, Annette
AU - Räikkönen, Katri
AU - Rathmann, Wolfgang
AU - Roden, Michael
AU - Schramm, Katharina
AU - Schwartz, Joel D.
AU - Starr, John
AU - Uitterlinden, André G
AU - Vokonas, Pantel
AU - Waldenberger, Melanie
AU - Yao, Chen
AU - Zhi, Degui
AU - Baccarelli, Andrea A
AU - Bandinelli, Stefania
AU - Deary, Ian
AU - Dehghan, Abbas
AU - Eriksson, Johan
AU - Herder, Christian
AU - Järvelin, Marjo-Riitta
AU - Levy, Daniel
AU - Arnett, Donna K
N1 - Title before publication: "Epigenome-wide study of circulating TNFα identifies robust methylation signals linked to incident coronary heart disease"
PY - 2018/4/4
Y1 - 2018/4/4
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 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.
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 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.
U2 - 10.1001/jamacardio.2018.0510
DO - 10.1001/jamacardio.2018.0510
M3 - Article
SN - 2380-6583
JO - JAMA Cardiology
JF - JAMA Cardiology
ER -