Epigenome-wide association study of circulating interleukin-6 connects DNA methylation to immunometabolic and inflammatory health

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.