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Epigenetic mechanisms underlying variation of IL-6, a well-established inflammation biomarker and risk factor for
Jessica I Lundin1, Ulrike Peters2, Yao Hu1
1Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Insights
Researchers identified novel DNA methylation sites linked to interleukin-6 (IL-6) levels, offering new insights into cardiovascular disease (CVD) mechanisms and potential therapeutic targets.
Area of Science:
- Genetics
- Immunology
- Cardiovascular Medicine
Background:
- Cardiovascular disease (CVD) is a leading cause of death globally, with chronic inflammation playing a key role.
- Interleukin-6 (IL-6) is a pro-inflammatory cytokine implicated in CVD pathophysiology.
- DNA methylation variations may explain differences in IL-6 levels and cardiovascular effects.
Purpose of the Study:
- To investigate the association between DNA methylation patterns and circulating IL-6 levels.
- To identify novel CpG sites related to IL-6 and their downstream effects.
- To explore potential causal links between methylation, IL-6, and CVD.
Main Methods:
- Analysis of methylated DNA (CpG sites) in relation to blood IL-6 levels.
- Study population comprised ~4,400 ancestrally diverse individuals.
- Utilized Mendelian randomization to infer causal effects.
Main Results:
- Identified 178 CpG sites associated with IL-6 levels.
- Discovered CpG sites within IL6R and linked to IL6/IL6ST transcripts.
- Functional analysis revealed pathways like cellular response to IL-6 and B-cell regulation.
- Identified genes associated with both CVD genetic components and IL-6 methylation.
- Mendelian randomization supported causal inference for three CpG sites, including LYN.
Conclusions:
- Several novel IL-6-CpG sites and methylation-affected pathways were identified.
- These findings enhance understanding of CVD pathophysiology.
- Further research on IL-6 regulation could reveal new therapeutic targets for CVD.
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.
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