Dataset Information

Epigenome-Wide Association Study of Soluble Tumor Necrosis Factor Receptor 2 Levels in the Framingham Heart Study.

ABSTRACT: Background: Transmembrane tumor necrosis factor (TNF) receptors are involved in inflammatory, apoptotic, and proliferative processes. In the bloodstream, soluble TNF receptor II (sTNFR2) can modify the inflammatory response of immune cells and is predictive of cardiovascular disease risk. We hypothesize that sTNFR2 is associated with epigenetic modifications of circulating leukocytes, which may relate to the pathophysiology underlying atherogenic risk. Methods: We conducted an epigenome-wide association study of sTNFR2 levels in the Framingham Heart Study Offspring cohort (examination 8; 2005-2008). sTNFR2 was quantitated by enzyme immunoassay and DNA methylation by microarray. The concentration of sTNFR2 was loge-transformed and outliers were excluded. We conducted linear mixed effects models to test the association between sTNFR2 level and methylation at over 400,000 CpGs, adjusting for age, sex, BMI, smoking, imputed cell count, technical covariates, and accounting for familial relatedness. Results: The study sample included 2468 participants (mean age: 67 ± 9 years, 52% women, mean sTNFR2 level 2661 ± 1078 pg/ml). After accounting for multiple testing, we identified 168 CpGs (P < 1.2 × 10-7) that were differentially methylated in relation to sTNFR2. A substantial proportion (27 CpGs; 16%) are in the major histocompatibility complex region and in loci overrepresented for antigen binding molecular functions (P = 1.7 × 10-4) and antigen processing and presentation biological processes (P = 1.3 × 10-8). Identified CpGs are enriched in active regulatory regions and associated with expression of 48 cis-genes (±500 kb) in whole blood (P < 1.1 × 10-5) that coincide with genes identified in GWAS of diseases of immune dysregulation (inflammatory bowel disease, type 1 diabetes, IgA nephropathy). Conclusion: Differentially methylated loci in leukocytes associated with sTNF2 levels reside in active regulatory regions, are overrepresented in antigen processes, and are linked to inflammatory diseases.

SUBMITTER: Mendelson MM

PROVIDER: S-EPMC5928448 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Epigenome-Wide Association Study of Soluble Tumor Necrosis Factor Receptor 2 Levels in the Framingham Heart Study.

Mendelson Michael M MM Johannes Roby R Liu Chunyu C Huan Tianxiao T Yao Chen C Miao Xiao X Murabito Joanne M JM Dupuis Josée J Levy Daniel D Benjamin Emelia J EJ Lin Honghuang H

Frontiers in pharmacology 20180424

<b>Background:</b> Transmembrane tumor necrosis factor (TNF) receptors are involved in inflammatory, apoptotic, and proliferative processes. In the bloodstream, soluble TNF receptor II (sTNFR2) can modify the inflammatory response of immune cells and is predictive of cardiovascular disease risk. We hypothesize that sTNFR2 is associated with epigenetic modifications of circulating leukocytes, which may relate to the pathophysiology underlying atherogenic risk. <b>Methods:</b> We conducted an epig ...[more]

PMID: 29740313

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Project description:ImportanceTumor 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.ObjectiveTo 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 participantsThis 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.ExposuresCirculating TNF-α concentration.Main outcomes and measuresDNA methylation at approximately 450 000 loci, neighboring DNA sequence variation, gene expression, and incident coronary heart disease.ResultsThe 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 relevanceWe 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.

Dataset Information

Epigenome-Wide Association Study of Soluble Tumor Necrosis Factor Receptor 2 Levels in the Framingham Heart Study.

Publications

Epigenome-Wide Association Study of Soluble Tumor Necrosis Factor Receptor 2 Levels in the Framingham Heart Study.

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