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

Michael M Mendelson,Joanne M Murabito,Emelia J Benjamin,Honghuang Lin,Daniel Levy,Chunyu Liu,Chen Yao,Xiao Miao,Josée Dupuis,Tianxiao Huan,Roby Johannes

doi:10.3389/fphar.2018.00207

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.

Highlights

Soluble tumor necrosis factor receptor II levels are associated with an extensive and diverse range of human diseases (Straczkowski et al, 2002; Turan et al, 2008; DoganavsargilBaysal et al, 2013)
After accounting for multiple testing, we identified 168 cytosine-phosphateguanine dinucleotides (CpGs) (P < 1.2 × 10−7) that were differentially methylated in relation to sTNFR2
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 genome-wide association studies (GWAS) of diseases of immune dysregulation

Summary

Introduction

Soluble tumor necrosis factor receptor II (sTNFR2) levels are associated with an extensive and diverse range of human diseases (Straczkowski et al, 2002; Turan et al, 2008; DoganavsargilBaysal et al, 2013). STNFR2 can modify the inflammatory response of immune cells. A greater understanding of the changes that occur in circulating leukocytes in relation to sTNFR2 levels may lead to improved mechanistic insights, enhanced disease predictive modeling, and highlight novel candidates for the development of therapeutics for CVD and inflammatory-related diseases. DNA methylation is an epigenetic modification that influences gene expression without changing the underlying genetic code. 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

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Discussion

Conclusion