The interplay between IL-18 rs1946518 polymorphism, TSH dysregulation, and vitamin D3 deficiency in Hashimoto's thyroiditis

Abstract

Background

Hashimoto's thyroiditis (HT) is an autoimmune thyroid disorder shaped by both genetic predisposition and environmental influences. One gene of growing interest is interleukin-18 (IL-18), particularly its rs1946518 (T/G) promoter polymorphism, which may affect inflammatory responses. Meanwhile, vitamin D3 has emerged as a key immunomodulatory factor, yet its interaction with genetic markers in HT remains unclear.

Objective

The primary objective of this study was to examine the potential role of the IL-18 gene promoter polymorphism (rs1946518, T/G) in the development of Hashimoto's thyroiditis (HT) among Iraqi patients. The investigation focused on whether this genetic variation affects serum IL-18 levels and contributes to immune and endocrine disturbances commonly observed in HT, including altered levels of thyroid-stimulating hormone (TSH), vitamin D3, and thyroid-specific autoantibodies (anti-TPO and anti-Tg). To further explore the functional implications of IL-18 in the disease process, molecular docking analysis was conducted to evaluate the potential interaction between IL-18 and active vitamin D3 [1,25(OH)₂D₃], aiming to examine the potential molecular interaction how vitamin D may modulate inflammatory responses in HT.

Methods

A total of 100 participants were included in a case-control design: 60 patients with HT and 40 matched health controls. Genotyping for rs1946518 was performed using Tetra-ARMS PCR. Serum levels of IL-18, 25(OH)D₃, TSH, anti-TPO, and anti-Tg were measured. Statistical comparisons and molecular docking analyses were conducted to understand both genetic and biochemical patterns.

Results

Carriers of the G allele showed significantly higher IL-18 levels, elevated TSH and autoantibodies, and lower vitamin D3 compared to TT/TG genotypes. Newly diagnosed patients had the highest IL-18 and lowest vitamin D3 concentrations. Molecular docking indicated a stable interaction between IL-18 and 1,25(OH)₂D₃, suggesting vitamin D might directly influence IL-18 function.

Conclusion

The IL-18 rs1946518 G allele may predispose individuals to stronger inflammatory activity in HT, while concurrent vitamin D3 deficiency could amplify this response.