Epigenetic mechanisms underlying variation of IL-6, a well-established inflammation biomarker and risk factor for cardiovascular disease

Abstract

Background and aims: Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, yet the underlying molecular mechanisms remain less understood. Chronic low-grade inflammation is a complex immune response contributing to the pathophysiology of cardiovascular disease. This response is signaled in part by interleukin-6 (IL-6), a pleiotropic, pro-inflammatory cytokine. Phenotypic variance in circulating IL-6 level may be explained in part by DNA methylation which is increasingly being associated with cardiovascular effects.

Methods: In this study we evaluated methylated DNA (CpG sites) associated with blood IL-6 levels across ∼4,400 ancestrally diverse individuals (81 % self-reported White; 9 % Black or African American, 8 % Hispanic or Latino/a, and 2 % Chinese American).

Results: We identified 178 CpG sites associated with IL-6 (p<0.05/∼395,000). Among the sites, cg04437762 is located within the transcription unit of IL6R, a current therapeutic target for inflammatory disease, and cg26692003 and cg00464927 were significant for IL6 and IL6ST trans-CpG-gene transcripts. Functional gene expression downstream of methylation identified cellular response to IL-6 and B-cell regulation and activation pathways. Four genes were linked with both a genetic component of cardiovascular disease and an IL-6 associated CpG site. Three CpG sites identified through Mendelian randomization analyses supported inference of a causal effect on IL-6 levels, including the LYN gene that regulates immune cell signaling and has been previously associated with atherosclerosis.

Conclusions: Overall, we identified several novel IL-6-CpG sites and downstream pathways affected by methylation. Follow-up functional studies including the regulation of IL-6 would complement current knowledge of CVD pathophysiology and potential therapeutic targets.