Lucy Sinke, Jenny van Dongen, Thomas Delerue, Rory Wilson, Yujing Xia, Marian Beekman, Gonneke Willemsen, Christian Gieger, Christian Herder, W. KOENIG, Annette Peters, Eco J. C. de Geus, J. M. Ordovas, Jordana T. Bell, Melanie Waldenberger, Dorret I. Boomsma, P. Eline Slagboom, Bastiaan T. Heijmans
Collectively, our results map the DNA methylation landscape surrounding circulating IL-6 levels and unveil directional effects and distinct functional relationships between epigenetics and inflammation.
Interleukin-6 (IL-6) drives metabolic and inflammatory processes central to disease. Current knowledge implicates epigenetic mechanisms in the regulation of these pathways, including through the methylation of CpG sites. This blood-based meta-analysis of three cohorts (n = 4,361) identifies 401 IL-6-associated CpGs enriched in regulatory regions and linked to key immunometabolic genes, including AIM2, MTOR, and IL6R. Three complementary causal inference approaches support most sites as responding to IL-6, with SOCS3 (Suppressor of Cytokine Signalling 3) methylation statistically mediating inflammatory bowel disease risk. Notably, one CpG connected to NFATC2IP (Nuclear Factor of Activated T-cells 2 Interacting Protein) plausibly influences both IL-6 production and multiple immunometabolic conditions, including body mass index and type 2 diabetes. Collectively, our results map the DNA methylation landscape surrounding circulating IL-6 levels and unveil directional effects and distinct functional relationships between epigenetics and inflammation.