Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Aslibekyan S

PROVIDER: S-EPMC6100733 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceAmerican Indian communities experience a high burden of coronary heart disease (CHD). Strategies are needed to identify individuals at risk and implement preventive interventions.ObjectiveTo investigate the association of blood DNA methylation (DNAm) with incident CHD using a large number of methylation sites (cytosine-phosphate-guanine [CpG]) in a single model.Design, setting, and participantsThis prospective study, including a discovery cohort (the Strong Heart Study [SHS]) and 4 additional cohorts (the Women's Health Initiative [WHI], the Framingham Heart Study [FHS], the Atherosclerosis Risk in Communities Study ([ARIC]-Black, and ARIC-White), evaluated 12 American Indian communities in 4 US states; African American women, Hispanic women, and White women throughout the US; White men and White women from Massachusetts; and Black men and women and White men and women from 4 US communities. A total of 2321 men and women (mean [SD] follow-up, 19.1 [9.2] years) were included in the SHS, 1874 women (mean [SD] follow-up, 15.8 [5.9] years) in the WHI, 2128 men and women (mean [SD] follow-up, 7.7 [1.8] years) in the FHS, 2114 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-Black, and 931 men and women (mean [SD] follow-up, 20.9 [7.2] years) in the ARIC-White. Data were collected from May 1989 to December 2018 and analyzed from February 2019 to May 2021.ExposureBlood DNA methylation.Main outcome and measureUsing a high-dimensional time-to-event elastic-net model for the association of 407 224 CpG sites with incident CHD in the SHS (749 events), this study selected the differentially methylated CpG positions (DMPs) selected in the SHS and evaluated them in the WHI (531 events), FHS (143 events), ARIC-Black (350 events), and ARIC-White (121 events) cohorts.ResultsThe median (IQR) age of participants in SHS was 55 (49-62) years, and 1359 participants (58.6%) were women. Elastic-net models selected 505 DMPs associated with incident CHD in the SHS beyond established risk factors, center, blood cell counts, and genetic principal components. Among those DMPs, 33 were commonly selected in 3 or 4 of the other cohorts and the pooled hazard ratios from the standard Cox models were significant at P < .05 for 10 of the DMPs. For example, the hazard ratio (95% CI) for CHD comparing the 90th and 10th percentiles of differentially methylated CpGs was 0.86 (0.78-0.95) for cg16604233 (tagged to COL11A2) and 1.23 (1.08-1.39) for cg09926486 (tagged to FRMD5). Some of the DMPs were consistent in the direction of the association; others showed associations in opposite directions across cohorts. Untargeted independent elastic-net models of CHD showed distinct DMPs, genes, and network of genes in the 5 cohorts.Conclusions and relevanceIn this multi-cohort study, blood-based DNAm findings supported an association between a complex blood epigenomic signature and CHD that was largely different across populations.

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