The etiology of HT has still not been fully understood. It has been considered as a genetic predisposition triggered by environmental factors that cause the loss of immunological tolerance, which attack the TFCs and lead to chronic inflammation with lymphocytic infiltration, especially T helper cells, destruction, atrophy, and fibrosis of TFCs [2, 3, 9]. Although immunological factors have been considered to play crucial roles in the pathogenesis of HT, the precise mechanisms by which such immunological factors contribute to that pathogenesis remain unknown. In this study, we sought to assess the potential roles of polymorphisms of IL18-137 and IL18-607 in patients with HT.
Some studies reported that HT is a Th1-driven autoimmune disease. IFN-γ and IL-2 measured both serum and intrathyroidal lymphocytes in HT patients. As a result, activated T cells secrete cytokines such as Interferon γ (IFN-γ) and interleukin 2 (IL-2), and they contribute to Th1-mediated immune response to the destruction of TFCs .
In addition to that, activated helper T lymphocytes interact with B lymphocytes, and activated B lymphocytes form antibodies that react with thyroid antigens. These have a role in the apoptotic destruction of thyroid cells through the activation of cytotoxic T cells (a Th1 function) [22, 23].
Also, serum concentrations of IL-2, INF-γ, IL-12, and IL-18 were found to be significantly increased in HT patients than in the control group . In another study, serum IL-18 levels in HT patients were not higher than those in controls, while patients with Grave’s disease had higher IL-18 levels than controls . We did not study IL-18 serum levels.
IL-18 was expressed in thyroid tissues of individuals with AIT by RT-PCR and immunohistology. It has been suggested that human TFCs increase IL-18 production, IL-18 together with IL-12, promotes INF-γ production in autoimmune thyroiditis. IFN-γ is essential for the development of lymphocytic autoimmune thyroiditis and the inhibition of thyrocyte proliferation . Before Liu et al., Kaiser et al., 2002 demonstrated IL-18 expression in animal models in autoimmune TFCs .
Carrying C at position − 607 and G at position − 137 were shown to be associated with a significantly higher expression of the IL-18 protein because the − 607C allele and the 137 G allele have high promoter activity [17, 20].
Inoue et al. did not find any differences in genotype and allele of polymorphism in -607 A/C between HT and controls but the frequency of the − 607CC genotype is higher severe HT than in mild HT. However, we found the IL18-607 C/A genotype polymorphism more common in controls than in the HT group. They also did not find any significant differences in the − 137 GC genotype and allele . Contrary to the findings of their study, we found that the − 137C/G polymorphism was more common among the cases than among the controls. This discrepancy might be due to ethnic differences.
Mukai et al. reported that they did not find any significant association between IL-18 polymorphism and AITD, especially Grave's disease . Ide et al. studied IL-18 polymorphism (-137 (G/C) and − 607 (C/A) in AITD in people with and without diabetes. They found differences between polymorphism and AITD  but we found the − 137C/G polymorphism to be more common among the cases than among the controls. This difference in the results might be due to the increased risk for HT. Also, the IL18-607 C/A genotype polymorphism was more common in the control than in the patients in the HT group. The CA genotype might have a protective effect against HT.
Huang et al. conducted a study on 116 pediatric patients in which they identified an association between HT and IL-18 in Taiwan in 2012. They studied the same IL-18 polymorphism G/C genotype is higher in HT than controls similarly in our study. In contrast, the G/G genotype was less frequent in patients with HT than in controls. They suggested that the G/G genotype might be protective against HT. They did not find any differences in the − 607 T/G genotype and allele between the two groups. They assumed that the C allele and CT haplotype are risks for HT tendency , but we did not find any significant differences in the allele groups.
Our findings show that the − 137 CG genotype is more frequent in patients with HT than in controls. The risk for HT patients was more than 2.237 times higher in individuals with the IL18 CG genotype than in those with the GG genotype. Also, the − 607 AC genotype is higher in controls than in the HT group. So, we suggested that the AC genotype might be protective for HT. Therefore, it is reasonable to speculate that polymorphism in the IL-18 promoter could affect the balance between Th1 and Th2 cytokine responses. The deterioration in the balance might have contributed to the destruction of TFCs in individuals carrying these genotypes of IL-18, leading to a higher susceptibility to HT.
According to the assessments to be made based on this study's findings, the CG genotype might represent a risk factor for HT. Conversely, there is a possibility that the AC genotype also plays a protective role against HT. New developments in the science of genetics will contribute to the emergence of new solutions by revealing the molecular and cellular mechanisms of HT. Therefore, further studies that include environmental factors will contribute to the explanation of many factors that we do not know today.