Introduction

Hashimoto’s thyroiditis (HT) is the first and most common organ-specific autoimmune disease described and its high prevalence varies according to the populations. An incidence of about 0.3 to 1.5 cases per 1,000 people per year is reported and is gradually increasing. Chabchoub et al. [1], estimate a prevalence of 22.8% in Africa. HT mainly occurs in young and middle-aged women. However, it can be diagnosed in patients of any age, including children [2–4].

Also known as chronic lymphocytic thyroiditis, HT was first described by Hashimoto H in 1912 as struma lymphomatosa. It is characterized by a lymphocyte infiltration of the thyroid parenchyma and the presence of anti-thyroid autoantibodies [5].

Currently, HT is believed being linked to multiple factors, including genetic susceptibility and environment. Among genetical factors, so far, several loci have been associated with HT, such as HLADR, immunoregulatory genes (CTLA-4, FoxP3, CD25, and PTPN22) and thyroid-specific genes [thyroglobulin (Tg)]. In addition, interferon-γ and inflammatory pathways [TNF-α and interleukin-6 (IL-6)] may also promote disease onset and development [3, 6, 7]. Indeed, IL-6, a pleiotropic cytokine with a wide range of biological activities, recognized in particular for its pro-inflammatory effects, is considered being a very important cytokine in the pathogenesis of thyroid autoimmunity, in part by its ability to induce Th17 cell differentiation, antibody production, cell activation, and modulation of thyroid cells function [8–10]. Furthermore, thyroid follicles constitutively produce IL-6. Its expression in thyroid cells correlated positively with the degree of lymphocyte infiltration in HT. This may contribute to the localization of the autoimmune response to the thyroid gland [8, 11, 12]. Therefore, SNPs (single nucleotide polymorphisms) of the IL-6 gene that can lead to an altered level of cytokine expression are considered as important candidates for susceptibility to Hashimoto’s disease.

Studies investigating the relationship between IL-6 gene polymorphism (rs1800795) and HT are inconclusive and few data are available in the literature. The aim of the present study is to investigate the association of IL-6 gene polymorphism (rs1800795) with the risk of developing HT in the population of Western Algeria.

Materials and methods

Results

In control group, the frequencies of all SNPs did not deviate significantly from those expected under Hardy-Weinberg equilibrium (P value = 0.66).

Discussion

IL-6 is a pleiotropic cytokine with a wide range of biological activities. It is produced by monocytes and macrophages, fibroblasts, keratinocytes, astrocytes, and endothelial cells. IL-6 plays an important role in regulating the adaptive immune response by stimulating antibody production and the development of effector T cells. IL-6, in combination with TGF-β, is essential for Th17 differentiation. It also impairs TGF-β-induced Treg differentiation. Thus, the upregulation of the Th17/Treg balance is considered being responsible for the disturbance of immunological tolerance, and is therefore pathologically implicated in the development of autoimmune diseases, including thyroid autoimmunity. Furthermore, thyroid follicles constitutively produce IL-6. Its expression in thyroid cells correlated positively with the degree of lymphocyte infiltration in HT. Additionally, IL-6 can act in a paracrine manner to modulate thyroid cell function. This may contribute to the localization of the autoimmune response to the thyroid gland [8, 11, 12].

The gene encoding for IL-6 is located on chromosome 7 at position 21 (Chr 7p21). It contains 5 exons separated by 4 introns. Genetic variants in the IL-6 gene promoter can have the potential to alter the regulation of the transcript production and expression of the cytokine. Considering the role of proinflammatory cytokines in the pathogenesis of the autoimmune response involved in HT, a change in the function or the quantity of IL-6 serum levels may lead to the initiation or perpetuation of the inflammatory process and then influencing an individual’s susceptibility to Hashimoto’s disease. For the IL-6 rs1800795 polymorphism, a functional SNP located at position -174 is linked to the constitutive transcription rate of IL-6, which could control its blood levels. A single nucleotide change from G to C at this position corresponds to a negative regulatory domain and results in downregulation of IL-6 transcription. Indeed, the presence of the G allele at position -174 has been found to be associated with high production of IL-6 and with an increased inflammatory response (GG/GC genotype carriers), whereas low production is observed with the C allele (homozygous CC genotype carriers) [13–15]. Thus, this polymorphism can be used as a functional variant to explore the causative role of elevated levels of IL-6 in many common diseases and can further explain the susceptibility of certain populations to different inflammatory and autoimmune diseases.

Our results report no significant associations of IL-6 (-174 G/C) genetic variants (at the allelic and genotypic level) between patients with Hashimoto’s disease and controls (P > 0.05). Nevertheless, conflicting data were reported in the literature concerning the genotypic and allelic frequencies of the IL-6 (-174 G/C) polymorphism in HT (Tables 5 and 6). In fact, in disagreement with our findings, Erdogan et al. [16] report that the rs1800795 polymorphism of the IL-6 gene promoter may represent a potential “candidate” genetic marker to predict the susceptibility of an individual to HT with a significantly different genotypic distribution between control group and HT patients (P < 0.001). This could be explained by an ethnic bias because the control group had a different distribution of genotypes (predominance of the CG genotype vs. GG genotype in our study). Moreover, certain polymorphisms have population-specific effects, and the Algerian population may lack other interacting genetic or environmental factors that would make IL-6 (-174 G/C) relevant to HT susceptibility. However, the results of the allelic distribution are similar to ours with no significant association (P > 0.05) with the susceptibility to HT [16].

Baki et al. [17] on their side investigated whether polymorphisms of cytokine genes TNF-α -308, IL-6 -174 and IL-10 -1082 are associated with HT. They concluded that there is no significant risk to HT afflicted by these polymorphisms alone (including IL-6 -174 G/C), again in agreement with our genetic results. Interestingly, their results rather suggest that the combined effects of the variant TNF-α -308, IL-6 -174 and IL-10 -1082 alleles may be more decisive in inducing functional differences and changing the risk of HT. Thus, the concomitant presence of mutant alleles IL-10 -1082A and IL-6 -174C multiplies by three the risk of HT [17]. Durães et al. [18] report in their study a significant association of the C allele in IL-6 (-174 G/C) with the risk of developing HT in a log-additive model (OR = 1.28; 95% CI = 1.06–1.54; P value = 8.96 × 10^–3). Their results also indicate that a combination of TNF-α (-308 G/A) and IL-6 (-174 G/C) genotypes reveals an increased risk for individuals harboring more than one high-risk allele/genotype for HT [18]. Thus, the association of IL-6 (-174 G/C) variants with HT susceptibility might not be due to polymorphism within the gene alone, but to a cumulative effect of cytokines genes variants.

In discussing the differences between local studies, it is important to highlight both the geographic and potential sociocultural distinctions. Our study focuses on a West Algerian population, while the one conducted by Aberkan [19] in 2016, focuses on a Central Algerian (Blida) population. While significant ethnic differences between the two regions may not exist, differences in environmental exposures and socio-cultural practices—such as dietary habits and lifestyle—could potentially influence the expression of genetic markers (i.e., an epigenetic effect), which could justify expecting some differences in results between these populations. Central Algeria, with its urban and diverse cultural interactions due to its capital status, contrasts with Western Algeria, where more specific regional or tribal customs may persist.

The consistency in genotypic and allelic frequencies of IL-6 gene polymorphism observed between the two studies (Tables 5 and 6) points to significant genetic homogeneity across Algerian populations, suggesting that IL-6 (-174 G/C) polymorphism frequencies may be relatively stable across Algerian regions. Additionally, neither study found a significant association between the IL-6 (-174 G/C) polymorphism and HT (P > 0.05) indicating that this polymorphism may not be a major genetic risk factor for HT in the broader Algerian population.

Current data suggest that the C allele at position -174 is responsible for lower expression of IL-6, leading to decreased serum levels. However, studies have shown that patients with HT have higher IL-6 serum levels inversely correlated with the thyroid function and hormone secretion [6, 20, 21].

Some studies have been performed to assess the association of another SNP in the IL-6 promoter region at position -572 C/G (rs1800796) with susceptibility to HT. No significant association was identified in HT patients, according to Mestiri et al. [22] in Tunisia. However, Inoue et al. [23] demonstrated an association between CG and GG genotypes and Hashimoto’s disease and its prognosis. Similar reports in a Chinese population suggest that IL-6 (-572 C/G) may be a potential genetic marker (heterozygous genotype CG) for susceptibility to Hashimoto’s disease [24].

In conclusion, there is no conclusive evidence that the IL-6 (-174 G/C) polymorphism is a causal variant of HT. Although, several factors are thought to interfere in the susceptibility and initiation of the disease while others are responsible for the perpetuation and enhancement of the autoimmune process. Since HT is a multifactorial disease, a combination of several elements can be at the origin of the susceptibility to the disease and/or its prognosis.