Abstract 18708: Novel DNA Methylation Loci Associated With Circulating Tumor Necrosis Factor-alpha, a Marker of Systemic Inflammation
Tumor necrosis factor alpha (TNFa) is a key regulator of the inflammatory response and a therapeutic target in a variety of disease settings, including cardiovascular conditions such as congestive heart failure and coronary artery disease. Despite its pathophysiologic relevance and an estimated heritability of over 60%, data on genetic and epigenetic determinants of circulating TNFa remain sparse. We conducted the first epigenome-wide meta-analysis of blood-derived DNA methylation and TNFa levels, using data at 450,000 loci from six cohorts participating in the CHARGE Epigenetics Working Group (total n= 6592). We natural log-transformed TNFa levels and fit linear mixed models adjusting for age, sex, family relatedness (where necessary), technical covariates, and cell count composition. We then performed fixed effects meta-analysis and found differential DNA methylation at six CpG sites to be associated with circulating TNFa after Bonferroni correction for multiple testing (P<1.1x10-7). Significant associations were consistent across cohorts. Findings were enriched for genes implicated in the immune response. Specifically, the top two CpG sites were located in the promoter region of NLRC5, a transactivator of major histocompatibility complex class I genes (P=5x10-11 and P=3x10-9 for cg16411857 and cg07839457, respectively, both located on the north shore of a CpG island). Another association was observed on chromosome 3, in the 5’UTR region of the DTX3L-PARP9 complex in the interferon signaling pathway (3 significant CpGs, top P=3x10-8 for cg01082299). This pathway was represented by another significant hit (cg21549285, P=4x10-8), located in the 5’UTR region of the MX1 gene, which encodes an interferon-induced GTP-binding protein. All significant CpGs were negatively associated (P<0.005) with incident coronary heart disease in a fixed effects meta-analysis of CHARGE cohorts (1229 events in 9871 participants). We present preliminary evidence of biologically plausible epigenetic correlates of circulating TNFa in multiple large community-based cohorts. These findings are candidates for functional validation as epigenetic targets for TNFa-related disorders and as biomarkers of cardiovascular and inflammatory disease.
Author Disclosures: S. Aslibekyan: None. G. Agha: None. S. Ligthart: None. T. Tanaka: None. E. Colicino: None. I.J. Deary: None. C. Marzi: None. M. Mendelson: None. R. Joehanes: None. J. Schwartz: None. M. Waldenberger: None. C. Herder: None. H. Lin: None. P. Vokonas: None. C. Liu: None. J. Dupuis: None. J. Meigs: None. A. Baccarelli: None. S. Bandinelli: None. D. Levy: None. R. Marioni: None. D. Arnett: None.
- © 2016 by American Heart Association, Inc.