Association of the −31C/T functional polymorphism in the interleukin-1β gene with the intractability of Graves' disease and the proportion of T helper type 17 cells

Abstract

SummaryInterleukin (IL)-1b is a proinflammatory cytokine and has been implicated in the pathogenesis of several autoimmune diseases. To evaluate the hypothesis that the functional -31C/T polymorphism (rs1143627) in the gene encoding IL-1b is associated with the intractability and the severity of autoimmune thyroid diseases, we genotyped this polymorphism in 64 patients with intractable Graves' disease (GD), 28 GD patients in remission, 49 patients with Hashimoto's disease (HD) who developed hypothyroidism (severe HD), 28 untreated euthyroid HD patients (mild HD) and 59 healthy volunteers. The -31T allele, which is related to the high producibility of IL-1b, was significantly more frequent in patients with intractable GD than in those with GD in remission (P = 0·0017; odds ratio 2·8; 95% confidence interval 1·5-5·3), although there was no difference in this frequency between two groups of HD patients. We showed additionally that the proportion of IL-17-producing T helper type 17 (Th17) cells, whose differentiation and proliferation are promoted by IL-1b, was higher in autoimmune thyroid disease patients with the T allele than in those with CC genotypes. In conclusion, our data indicated that the T allele of -31C/T polymorphism in the IL1B gene was involved in the intractability of GD, and this involvement may arise through the differentiation and proliferation of Th17 cells.

Association of polymorphisms in the <i>ICOS</i> and <i>ICOSL</i> genes with the pathogenesis of autoimmune thyroid diseases

“…In our study, the proportion of Th17 cells was higher in patients with AITD than in control subjects, and was also higher in patients with intractable GD than in patients with GD in remission [3]. Furthermore, the alleles of the SNPs in IL-1β [37] and TGF-β [35], which induce Th17 predominance, were more frequent in patients with intractable GD than in those with GD in remission. Moreover, ICOS + Treg have stronger suppressive activity and superior survival than ICOS -Treg [24].…”

Functional polymorphisms affecting Th1 differentiation are associated with the severity of autoimmune thyroid diseases

“…However, the −607 CC genotype was also found significantly more frequently in GD patients in remission than in patients with intractable GD. We previously reported that Th17 cells and inflammatory cytokines, such as IL-1β, that induce Th17 differentiation were associated with the intractability of GD [8,39,40]. We also reported that lower genetic expression of TBX21, which promotes the differentiation of Th1, was associated with the intractability of GD [11], probably because IFN-γ, a Th1 cytokine, potently inhibits the development of Th17 cells [41].…”

Association of polymorphisms in DNMT1, DNMT3A, DNMT3B, MTHFR and MTRR genes with global DNA methylation levels and prognosis of autoimmune thyroid disease

“…In addition, we have reported previously that genetic programming for production of higher interleukin (IL)-1b and transforming growth factor (TGF)-b levels are associated with intractability of GD [26,27]. It is well known that demethylation of the CpG site in the promoter regions enhance gene expression [28,29].…”