Autoantibodies against complement C1q correlate with the thyroid function in patients with autoimmune thyroid disease

Autoantibodies against complement C1q (anti-C1q) have been well described in patients with systemic lupus erythematosus, where they correlate with the occurrence of severe lupus nephritis. However, data on anti-C1q in organ-specific autoimmune diseases are scarce. In order to determine the prevalence of anti-C1q in patients with autoimmune thyroid disorders (AITD) and a possible association with thyroid function, we measured prospectively anti-C1q in 23 patients with Graves' disease (GD) and 52 patients with Hashimoto's thyroiditis (HT). Anti-C1q levels were correlated with parameters of thyroid function and autoantibodies against thyroperoxidase, thyroglobulin and thyroid stimulating hormone (TSH) receptor. Twenty-one patients with multi-nodular goitre and 72 normal blood donors served as controls. We found elevated concentrations of anti-C1q more frequently in patients with AITD than in controls: seven of 23 (30%) patients with GD and 11 of 52 (21%) patients with HT, compared with one of 21 (5%) patients with multi-nodular goitre and six of 72 (8%) normal controls. Anti-C1q levels did not correlate with thyroid autoantibodies. However, in GD absolute levels of anti-C1q correlated negatively with TSH and positively with free thyroxine (FT4) and triiodothyronine (FT3). In contrast, in HT, anti-C1q correlated positively with TSH levels. No correlation between TSH and thyroid autoantibodies was found. In conclusion, we found an increased prevalence of anti-C1q in patients with AITD and their levels correlated with the thyroid function in both GD and HT. This correlation seems to be independent of thyroid autoantibodies. Therefore, anti-C1q might point to a pathogenic mechanism involved in the development of AITD that is independent of classical thyroid autoantibodies.     

Vitamin D and autoimmune thyroid diseases

The role of vitamin D as an immune modulator has been emphasized in recent years, and low levels of the hormone were observed in several autoimmune diseases including multiple sclerosis and systemic lupus erythematosus. Vitamin D mediates its effect though binding to vitamin D receptor (VDR), and activation of VDR-responsive genes. While VDR gene polymorphism was found to associate with autoimmune thyroid diseases (AITDs), few studies examined levels of vitamin D in these patients and those that did yielded conflicting results. We therefore undertook to evaluate the levels of vitamin D in patients with AITDs compared to patients with non-AITDs and healthy controls. Serum vitamin D (25-OH) levels were measured in 50 patients with AITDs, 42 patients with non-AITDs and 98 healthy subjects, utilizing the LIAISON chemiluminescence immunoassay (DiaSorin, Saluggia, Italy). Vitamin D deficiency was designated at levels lower than 10 ng/ml. Antithyroid antibodies, thyroid functions and demographic parameters were evaluated in all patients. The prevalence of vitamin D deficiency was significantly higher in patients with AITDs compared with healthy individuals (72% versus 30.6% P<0.001), as well as in patients with Hashimoto''s thyroiditis compared to patients with non-AITDs (79% versus 52% P<0.05). Vitamin D deficiency also correlated to the presence of antithyroid antibodies (P=0.01) and abnormal thyroid function tests (P=0.059). Significantly low levels of vitamin D were documented in patients with AITDs that were related to the presence of anti thyroid antibodies and abnormal thyroid function tests, suggesting the involvement of vitamin D in the pathogenesis of AITDs and the advisability of supplementation.     

Serum CXCL10 levels and neuromuscular manifestations in patients with autoimmune thyroid diseases

Objective: Serum C-X-C motif chemokine 10 (CXCL10) levels have been shown to be elevated in autoimmune thyroid diseases (AITD). This study sought to determine whether newly diagnosed AITD patients with neuromuscular findings had higher levels of CXCL10 than those without neuromuscular manifestations.

Design: A total of 80 patients were recruited to the study, which included treatment-naive hypothyroid Hashimoto's thyroiditis (n = 19) and hyperthyroid Graves' disease (GD; n = 21), euthyroid thyroid autoantibody-positive (n = 20) and -negative (n = 20) patients.

Methods: All patients underwent a thorough sensorimotor and neuromuscular examination. Serum samples were kept in ? 20°C for further CXCL10 measurements with ELISA.

Results: There was a significant difference with regard to serum CXCL10 levels only between GD and euthyroid thyroid autoantibody-negative patient groups [187(12-418) vs. 37.5(2-542) pg/ml, p < 0.05]. However, a comparison of newly diagnosed AITD patients with and without neuromuscular manifestations in terms of serum CXCL10 levels yielded no significant difference. When a correlation of existence of a neuromuscular manifestation and serum CXCL10 levels was evaluated, a significantly positive correlation was noted between carpal tunnel syndrome (CTS) and serum CXCL10 levels [207 (95-748) pg/ml in CTS-positive vs. 117 (2-977) pg/ml in CTS-negative patients, p < 0.05].

Conclusions: In this study, from a number of neuromuscular manifestations, only the existence of CTS correlated with significantly higher CXCL10 levels in the whole study group. Further studies with larger numbers of patients with autoimmune-based hyper- and hypothyroidism may better clarify the hypothesis regarding a relationship between serum CXCL10 levels and neuromuscular manifestations of AITD.     

Inclusion of ALKBH5 as a candidate gene for the susceptibility of autoimmune thyroid disease

PurposeRNA demethylase AlkB homolog 5 (ALKBH5) gene is pivotal in N6-methyladenosine (m6A) modification. Therefore, this study aimed to explore the potential relationship between polymorphisms of ALKBH5 gene and the development of autoimmune thyroid disease (AITD).Material and methodsA case-control study of 979 AITD patients, including 620 Graves' disease (GD) and 359 Hashimoto's thyroiditis (HT), and 732 normal controls of the Chinese Han population was performed using high-throughput sequencing (HiSeq) genotyping method for detecting 5 variants in ALKBH5 gene (rs12936694, rs2124370, rs4925144, rs8068517, and rs9913266). In addition, the associations between ALKBH5 single nucleotide polymorphisms (SNPs) and clinical phenotypes of AITD were investigated.ResultsCompared to normal controls, rs9913266 displayed significant differences in allele and genotype distributions in AITD and GD. rs12936694 also showed significantly different frequencies of alleles in AITD and GD. The link of these 2 loci polymorprhisms to AITD and GD also existed after adjusting for age and gender. When stratified by sex, the minor allele of rs9913266 was associated with the risk of female AITD and HT development before and after adjusting for age and gender. There was a significant association between rs8068517 locus and GD in females after adjusting for the confounders. Finally, we observed significant correlations of haplotypes CGACA and CAGCG to the susceptibility of AITD and GD.ConclusionsOur results provided evidence of association of polymorphisms in ALKBH5 gene with AITD, GD, and HT patients, and hence ALKBH5 might be the candidate gene for susceptibility to AITD.     

The regulatory T cell gene FOXP3 and genetic susceptibility to thyroid autoimmunity: an association analysis in Caucasian and Japanese cohorts

FOXP3 is a key gene in the development of regulatory T cells (Treg). FOXP3 expression commits naïve T cells to become Treg cells. Indeed, mutations in the FOXP3 gene cause severe systemic autoimmune diseases in humans and in mice. Therefore, we hypothesized that the FOXP3 gene may be associated with thyroid autoimmunity which is among the typical autoimmune diseases that develop in individuals with FOXP3 mutations. Moreover, the FOXP3 gene is located within an X-chromosome locus (Xp11.23) previously shown to be linked with autoimmune thyroid diseases (AITD). We tested the FOXP3 gene locus for association with AITD in two large cohorts of US Caucasians and Japanese AITD patients. We analyzed 269 Caucasian AITD patients (52 males and 217 females) and 357 Caucasian controls (159 males and 198 females), as well as 377 female Japanese AITD patients and 179 female Japanese controls. The FOXP3 gene locus was analyzed using four microsatellite polymorphisms [(GT)n; (TC)n; DXS573; DXS1208] flanking the FOXP3 gene locus. Interestingly, while no association was found between FOXP3 polymorphisms and AITD in the Japanese cohort there was a significant association in the Caucasian cohort. There was a significant association of the (TC)n polymorphism with AITD in the Caucasian male AITD patients (p = 0.011; 5 degrees of freedom [df]). Similarly, there was an association between the DXS573 microsatellite and AITD in the Caucasian female AITD patients (p = 0.00023; 4 df). These results suggest that polymorphisms of the FOXP3 gene may play a role in the genetic susceptibility to AITD in Caucasians, perhaps by altering FOXP3 function and/or expression.     

Association of MBL2 gene exon 1 variants with autoimmune thyroid disease in Brazilian patients

We investigated the association between MBL2 gene exon 1 functional polymorphisms and autoimmune thyroid disease (AITD) in 163 Brazilian patients (87 with Hashimoto thyroiditis, HT; 76 with Graves' disease) and 214 healthy controls. Individuals carrying MBL2 O allele are at higher risk of developing AITD (OR = 1.58, 95% CI: 1.11-2.26; P-value = 0.009) and HT (OR = 1.67, 95% CI: 1.09-2.55; P-value = 0.013) as suggesting a possible role for mannose-binding lectin in influencing disease susceptibility.     

Plasma VEGF-related polymorphisms are implied in autoimmune thyroid diseases

Autoimmune thyroid diseases (AITD), including Graves’ disease (GD) and Hashimoto thyroiditis (HT), are complex multifactorial diseases. Vascular endothelial growth factor (VEGF) is implicated in various inflammatory diseases, especially autoimmune diseases. Our aim was to elucidate the relationships between plasma VEGF levels and four genome-wide association study-identified single nucleotide polymorphisms (SNPs) related to VEGF with AITD in Tunisian patients. A total of 364 healthy controls and 389 patients with AITD were genotyped for the SNPs rs6921438, rs4416670, rs6993770 and rs10738760. Levels of thyroid hormones and antibodies were quantified simultaneously with plasma VEGF after a period of six months of treatment. We found that the minor alleles of rs10738760 and rs6921438 are associated with the presence of GD. A allele of rs10738760 polymorphism is associated with increased plasma levels of free tri-iodothyronin (FT3) while no relationship was found with circulating VEGF plasma levels after six months of treatment. We also showed that the T allele of rs4416670 polymorphism was associated with increased risk of hyperthyroidism in patients treated for six months, independently of their initial diagnosis. There was no significant association between the SNPs and the risk for HT compared with controls. This study shows that AITD are influenced by 3 SNPs linked to VEGF circulating levels. Whereas rs10738760 appeared specific to GD and FT3 production after six months of treatment, rs6921438 and rs4416670 were implicated in the risk for GD. This study opens new ways to test pharmacogenomics concepts in the future especially in GD in which recurrence prognosis is still challenging.     

Autoimmune thyroid diseases: genetic susceptibility of thyroid‐specific genes and thyroid autoantigens contributions

Autoimmune thyroid diseases are common polygenic multifactorial disorders with the environment contributing importantly to the emergence of the disease phenotype. Some of the disease manifestations, such as severe thyroid‐associated ophthalmopathy, pretibial myxedema and thyroid antigen/antibody immune complex nephritis are unusual to rare. The spectrum of autoimmune thyroid diseases includes: Graves’ disease (GD), Hashimoto's thyroiditis (HT), atrophic autoimmune thyroiditis, postpartum thyroiditis, painless thyroiditis unrelated to pregnancy and thyroid‐associated ophthalmopathy. This spectrum present contrasts in terms of thyroid function, disease duration and spread to other anatomic location. The genetic basis of autoimmune thyroid disease (AITD) is complex and likely to be due to genes of both large and small effects. In GD the autoimmune process results in the production of thyroid‐stimulating antibodies and lead to hyperthyroidism, whereas in HT the end result is destruction of thyroid cells and hypothyroidism. Recent studies in the field of autoimmune thyroid diseases have largely focused on (i) the genes involved in immune response and/or thyroid physiology with could influence susceptibility to disease, (ii) the delineation of B‐cell autoepitopes recognized by the main autoantigens, thyroglobulin, thyroperoxidase and TSH receptor, to improve our understanding of how these molecules are seen by the immune system and (iii) the regulatory network controlling the synthesis of thyroid hormones and its dysfunction in AITD. The aim of the present review is to summarize the current knowledge regarding the relation existing between some susceptibility genes, autoantigens and dysfunction of thyroid function during AITD.     

Thyroid cancer and thyroid autoimmune disease: A review of molecular aspects and clinical outcomes

Thyroid cancer (TC) is the most prevalent malignant neoplasm that affects the endocrine system. Hashimoto's thyroiditis (HT), also known as chronic lymphocytic thyroiditis, is the most common autoimmune thyroid disease (AITD) that, together with Graves' disease (GD), represent the main autoimmune diseases that affect the thyroid gland. Some studies suggest a greater risk of AITD and the development of TC, while others, investigate its relationship with TC progression and patient prognosis. In this review, we have analyzed published data on the molecular aspects related to the association between AITD and TC, addressing their influence on TC progression, diagnosis, and prognosis of the patients. MEDLINE database (PubMed) platform was used as a search engine and the original articles related to the topic were selected using the keywords combination “thyroid cancer and Hashimoto thyroiditis” or “thyroid carcinoma and thyroid autoimmune disease”. After the selection, we categorized the main findings of the papers into four topics: antitumor immunity, tumor progression, diagnosis, and prognosis. Although most of the studies have pointed out the presence of AITD as a factor that increases the risk of TC, few molecular mechanisms to support this conclusion have been described. Additionally, little information is available to explain, pathophysiologically, the effects of autoimmunity in TC diagnosis, progression, and prognosis.     

Autoimmune thyroid disorders and rheumatoid arthritis: A bidirectional interplay

Rheumatoid arthritis (RA) and autoimmune thyroid disease (AITD) can occur in the same patient in the autoimmune polyglandular syndrome 2. The association of the two conditions has been recognized long-time ago and the prevalence of AITD in patients with RA and vice versa is well assessed. Geographical variation of AITD and related autoantibodies in RA patients is partly due to ethnic and environmental differences of the studied populations. The impacts of thyroid disorders on RA outcome and vice versa are still controversy. In both AITD and RA genetic susceptibility and environmental factors play a synergic role in the development of the diseases. In this review we aimed at investigating the association of AITD and thyroid autoantibodies with RA, the common pathogenic pathways, the correlation with RA disease activity, and influence of the treatment.     

Association studies of the IL-23R gene in autoimmune thyroid disease in the Japanese population

Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are caused by interplays of genetic factors and environmental triggers. Interleukin-23 and its receptor (IL-23R) guide T cells towards the Th17 phenotype. IL-23R single nucleotide polymorphisms (SNPs) have been shown to be associated with several autoimmune diseases, including Crohn's disease and rheumatoid arthritis, and Graves' ophthalmopathy (GO) in Caucasians. To determine whether variants in the IL-23R gene are associated with AITDs in Japanese, 464 Japanese AITD patients (290 with GD, 174 with HT) and 179 matched Japanese control subjects were genotyped for four SNPs spanning the IL-23R gene. SNPs rs11209026 and rs7530511 were genotyped using TaqMan allelic discrimination assays and SNPs rs2201841 and rs10889677 were genotyped using a fluorescent-based restriction fragment length polymorphism method. Case-control association studies were performed using the χ² and Fisher's exact tests with Yates correction. Of the four SNPs rs11209026 was non-polymorphic in our dataset. The other three SNPs were not associated with GD or GO or HT in our Japanese population. These results suggest that the IL-23R gene is associated with AITDs only in a specific ethnic group.     

Anti‐C1q autoantibodies are linked to autoimmune thyroid disorders in pregnant women

Anti‐C1q antibodies (anti‐C1q) have been implicated in the pathogenesis of autoimmune diseases, including autoimmune thyroid disorders (AITD). The aim of this study was to evaluate the association between anti‐C1q and thyroid function in pregnancy‐associated AITD. In 96 pregnant women screened positive for AITD (thyroid dysfunction and/or antibodies against thyroperoxidase – TPOAb), anti‐C1q were measured during the 9‐11th gestational week and after delivery (median 16 months after delivery), and compared to the corresponding serum levels of thyroid hormones. As controls, 80 healthy pregnant women, 72 non‐pregnant AITD patients and 72 blood donors were included. In the non‐pregnant AITD group, two serum samples ≥ 6 months apart were analysed. Compared to blood donors, anti‐C1q levels were substantially higher in all pregnant women analysed. In pregnancy, anti‐C1q levels were higher in the TPOAb‐positive women than in controls (37 versus 17·5%, P < 0·0001). Anti‐C1q‐positive pregnant women screened positive for AITD had higher thyroid‐stimulating hormone (TSH) levels than anti‐C1q‐negative women (2·41 versus 1·94 mU/l, P = 0·01), and TSH correlated positively with anti‐C1q (r = 0·226, P = 0·045) in the TPOAb‐positive women. After delivery, serum levels of anti‐C1q decreased in the positively screened TPOAb‐negative women (8·8 versus 5·9 U/l, P = 0·002), but not in the TPOAb‐positive ones, and they no longer correlated with TSH. Anti‐C1q antibody levels increase during pregnancy in general and even more in the context of AITD, where they correlate with thyroid stimulating hormone levels.     

Increased prevalence of antibodies to enteropathogenic Yersinia enterocolitica virulence proteins in relatives of patients with autoimmune thyroid disease

Infections have been implicated in the pathogenesis of a number of autoimmune diseases, and Yersinia enterocolitica (YE) might play a role in the development of autoimmune thyroid disease (AITD). Clinical evidence in support of this hypothesis has been inconclusive. We reasoned that looking earlier in the natural course of AITD might enhance chances of finding evidence for YE infection. Consequently, we determined seroreactivity against YE in subjects at risk of developing AITD, i.e. in 803 female relatives of AITD patients in self-proclaimed good health. As a comparison group we used 100 healthy women who participated in a program for reference values. IgG and IgA antibodies to virulence-associated outer membrane proteins (YOPs) of YE were measured by a specific assay. Serum thyroid peroxidase antibodies (TPO-Ab) as indicators of AITD were considered to be positive at levels of> 100 kU/l. The prevalence of YOP IgG-Ab was higher in AITD relatives than in controls (40.1% vs. 24%, P = 0.002), and the same was true for YOP IgA-Ab (22% vs. 13%, P < 0.05). Of the 803 AITD relatives, 44 had an increased or decreased plasma TSH, and 759 were euthyroid as evident from a normal TSH; the prevalence of YOP-Ab did not differ between these three subgroups. TPO-Ab were present in 10% of controls and in 27% of the AITD relatives (P < 0.001). The prevalence of TPO-Ab in the euthyroid AITD relatives was not different between YOP IgG-Ab positive and negative subjects (23.3% vs. 24.7%, NS), nor between YOP IgA-Ab positive and negative subjects (21.2% vs. 24.9%, NS). In conclusion, healthy female relatives of AITD patients have an increased prevalence of YOP antibodies, which, however, is not related to the higher prevalence of TPO antibodies in these subjects. The findings suggest a higher rate of persistent YE infection in AITD relatives. Susceptibility genes for AITD may also confer a risk for YE infection.     

Immunogenetics of autoimmune thyroid diseases: A comprehensive review

Both environmental and genetic triggers factor into the etiology of autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT). Although the exact pathogenesis and causative interaction between environment and genes are unknown, GD and HT share similar immune-mediated mechanisms of disease. They both are characterized by the production of thyroid autoantibodies and by thyroidal lymphocytic infiltration, despite being clinically distinct entities with thyrotoxicosis in GD and hypothyroidism in HT. Family and population studies confirm the strong genetic influence and inheritability in the development of AITD. AITD susceptibility genes can be categorized as either thyroid specific (Tg, TSHR) or immune-modulating (FOXP3, CD25, CD40, CTLA-4, HLA), with HLA-DR3 carrying the highest risk. Of the AITD susceptibility genes, FOXP3 and CD25 play critical roles in the establishment of peripheral tolerance while CD40, CTLA-4, and the HLA genes are pivotal for T lymphocyte activation and antigen presentation. Polymorphisms in these immune-modulating genes, in particular, significantly contribute to the predisposition for GD, HT and, unsurprisingly, other autoimmune diseases. Emerging evidence suggests that single nucleotide polymorphisms (SNPs) in the immunoregulatory genes may functionally hinder the proper development of central and peripheral tolerance and alter T cell interactions with antigen presenting cells (APCs) in the immunological synapse. Thus, susceptibility genes for AITD contribute directly to the key mechanism underlying the development of organ-specific autoimmunity, namely the breakdown in self-tolerance. Here we review the major immune-modulating genes that are associated with AITD and their potential functional effects on thyroidal immune dysregulation.     

Celiac disease in North Italian patients with autoimmune thyroid diseases

Background: Patients with autoimmune thyroid diseases (AITDs) are prone to develop other autoimmune manifestations and to display autoimmune polyendocrine syndromes.

An increased prevalence of celiac disease (CD) was demonstrated in adult European and Italian patients with AITDs; conversely, an increased prevalence of AITDs was demonstrated in patients with CD. An IgA deficiency is the most frequent immunodeficiency in humans and, in general, high frequency of this disorder was demonstrated in those with autoimmune diseases.

Aim: To define the prevalence of both CD and IgA deficiency in North Italian patients with AITDs.

Methods: 276 Italian patients with AITD were enrolled (mean age 42.6 years range 12–89, 186 of whom had chronic thyroiditis and 90 had Graves' disease). The tissue transglutaminase autoantibodies of the IgA class (IgA-tTGAbs) were evaluated using an ELISA method in these patients. Furthermore, the serological levels of the IgA were determined.

Results: Five of the patients (1.8%) were affected by previously diagnosed CD and were on a gluten-free diet. Ten out of the remaining 271 patients (3.6%) were found to be positive for celiac-related autoantibodies. All of these patients agreed to undergo endoscopy and duodenal biopsies and silent CD was found in 5 of them but 5 had not histopathological signs of CD.

CD (clinical, silent or latent) was present in 15/276 (5.4%) of the North Italian patients with AITD; this prevalence is significantly higher with respect to the general population (p < 0.00001).

The genetic pattern of the 10 patients with both AITDs and CD was characterized by the presence of DQ2 in 8 patients and DQ8 in 2. An IgA deficiency was present in 2/276 of the patients (0.72%).

Conclusions: CD is significantly increased in patients with thyroid autoimmune disorders for this reason it is important to screen for CD in patients with AITDs.     

自身免疫性甲状腺疾病胰岛素样生长因子及其结合蛋白的改变

为探讨胰岛素样生长因子 (IGF )、胰岛素样生长因子结合蛋白 (IGFBP )在自身免疫性甲状腺疾病 (AITD )中的变化及其影响 ,本研究检测了 5 6例AITD患者与 2 4例正常对照血清IGF 1、IGFBP 1～ 3及甲状腺功能 ,发现IGF 1在GD、HT与GD控制组明显低于正常对照 (P <0 0 1) ,IGFBP 1、IGFBP 2在GD组明显高于正常对照 (P <0 0 1,0 0 5 ) ,IGFBP 3在HT组明显低于正常对照 (P <0 0 5 ) ;IGF 1与甲状腺激素间无相关 ,IGFBP 1～ 3均与TT4相关 (r =0 34、 0 38、 0 31;P <0 0 5 )。提示机体甲状腺激素、免疫状态均可能影响IGF、IGFBP水平 ,而后者有可能参与调节AITD的进程。     

Influx of recent thymic emigrants into autoimmune thyroid disease glands in humans

Autoimmune thyroid diseases (AITD) are considered as prototypic organ-specific autoimmune diseases, yet their underlying aetiology remains poorly understood. Among the various pathophysiological mechanisms considered, a failure of central tolerance has received little attention. Here we present evidence in favour of dysregulated thymic function playing a role in AITD. Flow-cytometric analyses conducted in peripheral blood lymphocytes from 58 AITD patients and 48 age- and-sex-matched controls showed that AITD patients have significantly higher blood levels of CD4(+)CD45RA(+), CD4(+)CD31(+) and CD4/CD8 double-positive T lymphocytes, all markers of recent thymic emigrants (RTE). In addition, the alpha-signal joint T cell receptor excision circles (TRECs) content (a molecular marker of RTEs) was higher in the group of AITD patients older than 35 years than in age-matched controls. This was independent from peripheral T cell expansion as assessed by relative telomere length. Comparisons of TREC levels in peripheral blood lymphocytes and intrathyroidal lymphocytes in paired samples showed higher levels within the thyroid during the initial 30 months of the disease, indicating an influx of RTE into the thyroid during the initial stages of AITD. Additionally, a lack of correlation between TREC levels and forkhead box P3 expression suggests that the intrathyroidal RTE are not natural regulatory T cells. These results uncover a hitherto unknown correlation between altered thymic T cell export, the composition of intrathyroidal T cells and autoimmune pathology.     

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

To clarify the association between factors regulating DNA methylation and the prognosis of autoimmune thyroid diseases (AITDs), we genotyped single nucleotide polymorphisms in genes encoding DNA methyltransferase 1 (DNMT1), DNMT3A, DNMT3B, methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), which are enzymes essential for DNA methylation. Subjects for this study included 125 patients with Hashimoto''s disease (HD), including 48 patients with severe HD and 49 patients with mild HD; 176 patients with Graves’ disease (GD), including 79 patients with intractable GD and 47 patients with GD in remission; and 83 healthy volunteers (control subjects). The DNMT1+32204GG genotype was more frequent in patients with intractable GD than in patients with GD in remission. Genomic DNA showed significantly lower levels of global methylation in individuals with the DNMT1+32204GG genotype than in those with the AA genotype. The MTRR+66AA genotype was observed to be more frequent in patients with severe HD than in those with mild HD. The DNMT1+14395A/G, DNMT3B−579G/T, MTHFR+677C/T and +1298A/C polymorphisms were not correlated with the development or prognosis of AITD. Our study indicates that the DNMT1+32204GG genotype correlates with DNA hypomethylation and with the intractability of GD, and that the MTRR+66AA genotype may correlate with the severity of HD.     

Association of interleukin-17A and -17F gene single-nucleotide polymorphisms with autoimmune thyroid diseases

Th17 lymphocyte and its relative cytokines have been shown to play an important role in autoimmune thyroid diseases (AITD). The aim of this study was to investigate the association between IL-17A and IL-17F gene polymorphisms and two main types of AITD, Graves' disease (GD) and Hashimoto's thyroiditis (HT). Whole blood specimens and clinical data were collected from 508 AITD patients (326 with GD and 182 with HT) and 224 age- and gender-matched healthy controls, respectively. IL-17A (rs2275913, rs8193037, rs3819025) polymorphism was determined using DNA sequencing method and IL-17F/rs763780 polymorphism was assayed by polymerase chain reaction-restriction fragment length polymorphism (PCR -RFLP). The results indicated that the frequencies of IL-17F/rs763780 genotypes in patients with GD and HT differed significantly from their controls (P = 0.013 and P = 0.005, respectively); the G allele frequencies were also significantly higher in the patient groups than the control groups (P = 0.002 and 0.001, respectively). For IL-17A/rs2275913 and rs8193037 SNP, no significant difference was observed in patients with either GD or HT compared to the control groups (P>0.05). Interestingly, for rs3819025, the frequency of A allele was lower in patients with GD than controls (P = 0.011). The frequencies of haplotype AGGG and GGGG in patients with GD and HT were significantly higher than in controls (P = 0.012, P = 0.019, P = 0.017 and P = 0.029, respectively). In conclusion, the results indicate that IL-17F/rs763780 polymorphisms may affect the susceptibility to AITD, and IL-17A/rs3819025 SNP is likely a protective factor to GD in the Chinese population.