Association of Methylation Signals With Incident Coronary Heart Disease in an Epigenome-Wide Assessment of Circulating Tumor Necrosis Factor α

<h3>Importance</h3> 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. <h3>Objective</h3> To conduct an epigenome-wide analysis of blood-derived DNA methylation and TNF-α levels and to assess the clinical relevance of findings. <h3>Design, Setting, and Participants</h3> 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. <h3>Exposures</h3> Circulating TNF-α concentration. <h3>Main Outcomes and Measures</h3> DNA methylation at approximately 450 000 loci, neighboring DNA sequence variation, gene expression, and incident coronary heart disease. <h3>Results</h3> 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<i>DTX3L-PARP9 </i>at cg00959259 (β [SE] = −0.01 [0.003];<i>P</i> = 7.36 × 10⁻⁸), cg08122652 (β [SE] = −0.008 [0.002];<i>P</i> = 2.24 × 10⁻⁷), and cg22930808(β [SE] = −0.01 [0.002];<i>P</i> = 6.92 × 10⁻⁸);<i>NLRC5</i>at cg16411857 (β [SE] = −0.01 [0.002];<i>P</i> = 2.14 × 10⁻¹³) and cg07839457 (β [SE] = −0.02 [0.003];<i>P</i> = 6.31 × 10⁻¹⁰); or<i>ABO</i>, at cg13683939 (β [SE] = 0.04 [0.008];<i>P</i> = 1.42 × 10⁻⁷) and cg24267699 (β [SE] = −0.009 [0.002];<i>P</i> = 1.67 × 10⁻⁷), after accounting for multiple testing. Of these, negative associations between TNF-α concentration and methylation of 2 loci in<i>NLRC5</i>and 1 in<i>DTX3L-14 PARP9</i>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;<i>P</i> = .003; cg07839457: HR, 0.89; 95% CI, 0.80-0.94;<i>P</i> = 3.1 × 10⁻⁵; cg00959259: HR, 0.91; 95% CI, 0.84-0.97;<i>P</i> = .002; cg08122652: HR, 0.81; 95% CI, 0.74-0.89;<i>P</i> = 2.0 × 10⁻⁵). <h3>Conclusions and Relevance</h3> 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.