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

## TL;DR

This study identifies DNA methylation sites linked to IL-6, a key player in inflammation and metabolism, and reveals how these epigenetic changes may influence disease risk.

## Contribution

The study maps IL-6-associated DNA methylation sites and uncovers causal relationships between methylation and immunometabolic conditions.

## Key findings

- 401 IL-6–associated CpGs were identified, enriched in regulatory regions and linked to genes like AIM2, MTOR, and IL6R.
- Methylation at SOCS3 statistically mediates inflammatory bowel disease risk.
- A CpG linked to NFATC2IP influences IL-6 production and conditions like BMI and type 2 diabetes.

## Abstract

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.

Meta-analysis and triangulation of causal evidence comprehensively map the DNA methylation landscape surrounding circulating IL-6 levels, with DNA methylation at SOCS3 highlighted as a potential mediator of IL-6 effects on inflammatory disease risk.