Association of Methylation Signals With Incident Coronary Heart Disease in an Epigenome-Wide Assessment of Circulating Tumor Necrosis Factor α.
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.
|Year of Publication||
2018 06 01
|PubMed Central ID||
WT_ / Wellcome Trust / United Kingdom
G1002319 / MRC_ / Medical Research Council / United Kingdom
Z99 AG999999 / Intramural NIH HHS / United States
MR/K026992/1 / Medical Research Council / United Kingdom
HHSN268201500001I / HL / NHLBI NIH HHS / United States
R01 ES021733 / ES / NIEHS NIH HHS / United States
R01 ES025225 / ES / NIEHS NIH HHS / United States
P30 ES023515 / ES / NIEHS NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
U01 DK078616 / DK / NIDDK NIH HHS / United States
G0500539 / MRC_ / Medical Research Council / United Kingdom
R01 HL087679 / HL / NHLBI NIH HHS / United States
BB/F019394/1 / Biotechnology and Biological Sciences Research Council / United Kingdom
CSO_ / Chief Scientist Office / United Kingdom
R00 ES023450 / ES / NIEHS NIH HHS / United States
K99 HL136875 / HL / NHLBI NIH HHS / United States
R01 HL104135 / HL / NHLBI NIH HHS / United States
G0600705 / MRC_ / Medical Research Council / United Kingdom