Are IL6 gene polymorphisms associated with increased risk of Hashimoto's thyroiditis?

Interleukin-6 (IL-6) is a multifunctional cytokine that plays a pivotal role in the transition from innate to adaptive immunity. Genetic variations in the IL6 gene, which influence cytokine production levels, have been extensively studied for their role in autoimmune thyroid diseases (AITD), including Hashimoto’s thyroiditis (HT) and Graves’ disease (GD).

Clinical evidence of susceptibility

Evidence from large-scale case-control studies and meta-analyses confirms a significant association between IL6 polymorphisms and increased risk for autoimmune thyroid conditions.

• The most studied variant, the rs1800795 (-174 G/C) polymorphism in the promoter region, is strongly linked to disease susceptibility. In a study of over 1,400 individuals, the C allele was significantly more frequent in Hashimoto’s thyroiditis patients than in healthy controls, with an odds ratio (OR) of 1.34 (95% CI: 1.07–1.68).
• The risk appears to be dose-dependent; individuals carrying two copies of the risk allele (CC genotype) demonstrated a significantly higher risk (OR=2.27) compared to those with other genotypes.
• In broader AITD contexts, such as Graves’ disease, meta-analyses have reported even stronger associations, with homozygous models showing an OR of 2.714, suggesting a robust shared genetic architecture across different thyroid autoimmune presentations.

Mechanistic explanations

The association between IL6 polymorphisms and Hashimoto’s thyroiditis is grounded in the cytokine's role in maintaining the balance between pro-inflammatory and regulatory immune responses.

• The rs1800795 polymorphism alters the transcriptional activity of the IL6 gene, typically leading to increased IL-6 expression and a subsequent pro-inflammatory environment.
• Elevated IL-6 levels facilitate the differentiation of Th17 cells, which are primary drivers of the chronic inflammation and tissue destruction seen in thyroid follicles.
• IL-6 also influences B-cell maturation and autoantibody production, while simultaneously impairing the function of regulatory T cells (Tregs), thereby facilitating the breakdown of self-tolerance.

Bottom line

• The association between IL6 gene polymorphisms (specifically rs1800795) and increased susceptibility to Hashimoto’s thyroiditis is supported by high-quality genetic data, with the risk allele significantly increasing the likelihood of disease development through the promotion of Th17-mediated inflammation.