Is DNA methylation in peripheral blood cells associated with circulating tumor necrosis factor α levels and risk of coronary heart disease?
In this epigenome-wide study, top methylation loci associated with circulating tumor necrosis factor α concentration in whole blood or CD4+ T cells were located in or near the DTX3L-PARP9 gene complex, NLRC5, and ABO. The findings in NLRC5 and DTX3L-PARP9 were successfully replicated and linked to gene expression, and methylation at these loci was robustly inversely associated with the risk of incident coronary heart disease.
After further validation, these epigenetic associations might be useful in the pursuit of new or improved therapeutic applications.
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.
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.
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.
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.
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
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