Polymorphisms of IKZF3 Gene and Autoimmune Thyroid Diseases: Associated with Graves’ Disease but Not with Hashimoto’s Thyroiditis

Background/Aims: The IKZF3 gene encodes a zinc-finger protein that plays an important role in the proliferation and differentiation of B lymphocytes. Autoimmune thyroid diseases (AITDs), mainly include Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), are probably caused by the aberrant proliferation of B cells. The objective of this study was to explore the association between IKZF3 polymorphisms and AITDs. Methods: We examined 915 AITD patients (604 GD and 311 HT) and 814 healthy controls. IKZF3 variants (rs2941522, rs907091, rs1453559, rs12150079 and rs2872507) were tested by PCR-ligase detection reaction. Results: It was manifested that that the minor alleles of the five loci increased susceptibility to GD (p<0.05 for rs2941522, and p<0.01 for rs907091, rs1453559, rs12150079 and rs2872507) but in HT patients, these loci showed no significant difference compared with controls. Similarly, the genotype distributions of GD patients manifested obvious differences in all these loci compared with the control group, whereas no statistical differences were observed between HT patients and controls. Furthermore, bioinformatics tools were used to analyze rs1453559, rs12150079 and rs907091. These variants were believed to be the transcription regulator. Conclusion: It is the first time we reported the association between the IKZF3 polymorphisms and GD, indicating that IKZF3 gene tends to bean important risk factor for the development of GD.

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IRF7 Gene Variations Confer Susceptibility to Autoimmune Thyroid Diseases and Graves’ Ophthalmopathy

International Journal of Endocrinology ◽

10.1155/2019/7429187 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7

Author(s):

Qiuming Yao ◽

Xiaofei An ◽

Jing Zhang ◽

Kaida Mu ◽

Ling Li ◽

...

Keyword(s):

Hashimoto’S Thyroiditis ◽

Susceptibility Gene ◽

Thyroid Diseases ◽

Minor Allele ◽

Hashimoto's Thyroiditis ◽

Graves Disease ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Graves Ophthalmopathy ◽

Significant Difference

The objective of this study was to investigate whether IRF7 polymorphisms are associated with autoimmune thyroid diseases (AITDs). We selected three single nucleotide polymorphisms (SNPs) of IRF7, namely, rs1061501, rs1131665, and rs1061502 for genotyping using PCR-based ligase detection reaction (LDR) method in a total of 1659 participants (592 with Graves’ disease, 297 with Hashimoto’s thyroiditis, and 770 healthy controls). Gene-disease and genotype-clinical phenotype associations were evaluated for the three SNPs. Our results showed that the AG genotype and the minor allele G frequency of rs1131665 and rs1061502 in AITD patients were both higher than those of the controls (rs1131665: AG genotype: P=0.017, OR=1.968; allele G: P=0.018, OR=1.946; rs1061502: AG genotype: P=0.029, OR=1.866; allele G: P=0.031, OR=1.847). Subgroup analysis also showed that the AG genotype and the minor allele G frequency of rs1131665 and rs1061502 in Graves’ disease patients were both higher than those of the controls (rs1131665: AG genotype: P=0.015, OR=2.074; allele G: P=0.016, OR=2.048; rs1061502: AG genotype: P=0.034, OR=1.919; allele G: P=0.035, OR=1.898). Furthermore, the allele G frequency of rs1061501 was associated with Graves’ ophthalmopathy (P=0.035, OR=1.396). No significant difference in IRF7 polymorphisms was found between Hashimoto’s thyroiditis patients and controls. Our study has revealed for the first time that IRF7 is a susceptibility gene for AITD, especially for Graves’ disease and Graves’ ophthalmopathy.

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Polymorphisms in Autophagy-Related Gene IRGM Are Associated with Susceptibility to Autoimmune Thyroid Diseases

BioMed Research International ◽

10.1155/2018/7959707 ◽

2018 ◽

Vol 2018 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Qiu-ming Yao ◽

Yuan-feng Zhu ◽

Wen Wang ◽

Zhen-yu Song ◽

Xiao-qing Shao ◽

...

Keyword(s):

Hashimoto’S Thyroiditis ◽

Susceptibility Gene ◽

Thyroid Diseases ◽

Hashimoto's Thyroiditis ◽

Graves Disease ◽

Related Gene ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Significant Difference ◽

Disease Associations

Background. To date, studies have shown that polymorphisms in an autophagy-related gene, IRGM, are linked with different diseases, especially autoimmune diseases. The present study aimed to examine the roles of IRGM polymorphisms in autoimmune thyroid diseases (AITD). Methods. Three polymorphisms in IRGM gene (rs10065172, rs4958847, and rs13361189) were genotyped in 1569 participants (488 with Graves’ disease, 292 with Hashimoto’s thyroiditis, and 789 healthy controls) using PCR-based ligase detection reaction method. Gene-disease associations were evaluated for the three SNPs. Results. T allele of rs10065172, A allele of rs4958847, and C allele of rs13361189 were all higher in Graves’ disease patients than controls, and the ORs were OR = 1.207 (P=0.022), OR = 1.207 (P=0.027), and OR = 1.200 (P=0.027), respectively. After adjusting for sex and age, rs10065172 and rs13361189 were still associated with GD under both the allele model and dominant model, and the adjusted ORs for rs10065172 were 1.20 (P=0.033) and 1.33 (P=0.024), while the adjusted ORs for rs13361189 were 1.19 (P=0.042) and 1.33 (P=0.026), respectively. No significant difference was found between Hashimoto’s thyroiditis patients and controls. Haplotype analysis found that CTA frequency was distinguishingly higher in Graves’ disease patients (OR = 1.195, P=0.030). The frequency of TCG haplotype was distinguishingly lower in AITD and Graves’ disease patients (OR = 0.861, P=0.044; OR = 0.816, P=0.017). Conclusions. Our study reveals IRGM as a susceptibility gene of AITD and Graves’ disease for the first time.

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Defect of a subpopulation of natural killer immune cells in Graves’ disease and Hashimoto’s thyroiditis: normalizing effect of dehydroepiandrosterone sulfate

Acta Endocrinologica ◽

10.1530/eje.1.01906 ◽

2005 ◽

Vol 152 (5) ◽

pp. 703-712 ◽

Cited By ~ 15

Author(s):

Sebastiano Bruno Solerte ◽

Sara Precerutti ◽

Carmine Gazzaruso ◽

Eleonora Locatelli ◽

Mauro Zamboni ◽

...

Keyword(s):

Nk Cells ◽

Hashimoto’S Thyroiditis ◽

Nk Cell ◽

Secretory Activity ◽

Thyroid Diseases ◽

Hashimoto's Thyroiditis ◽

Graves Disease ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Tnf Α

Background: The study of the natural killer (NK) immune compartment could provide important findings to help in the understanding of some of the pathogenetic mechanisms related to autoimmune thyroid diseases (Graves’ disease (GD) and Hashimoto’s thyroiditis (HT)). Within this context, it was suggested that alterations in NK cell cytotoxicity (NKCC) and NK production of cytokines might occur in subjects with GD and HT, whereas the normalization of NK functions could potentially contribute to the prevention of the onset or the progression of both diseases. Objective: Due to the hypothesis of alterations in NK in autoimmune thyroid diseases, we were interested to evaluate NKCC in GD and HT patients and to modulate NK function and secretory activity with cytokines and dehydroepiandrosterone sulfate (DHEAS) in an attempt to normalize NK cell defect. Design: We studied 13 patients with recent onset Graves’ disease, 11 patients with Hashimoto’s thyroiditis at first diagnosis and 15 age-matched healthy subjects. Methods: NK cells were concentrated at a density of 7.75 × 106 cells/ml by negative immunomagnetic cell separation and validated by FACScan as CD16 + /CD56 + cells. NK cells were incubated with interleukin-2 (IL-2) and interferon-β (IFN-β) and co-incubated with DHEAS at different molar concentrations for measuring NKCC and the secretory pattern of tumor necrosis factor-α (TNF-α) from NK cells. Results: Lower spontaneous, IL-2- and IFN-β-modulated NKCC was demonstrated in GD and HT patients compared with healthy subjects (P < 0.001). A decrease in spontaneous and IL-2-modulated TNF-α release from NK cells was also found in both groups of patients (P < 0.001). The co-incubation of NK cells with IL-2/IFN-β + DHEAS at different molar concentrations (from 10−8 to 10−5 M/ml/NK cells) promptly normalized NKCC and TNF-α secretion in GD and HT patients. Conclusions: A functional defect of a subpopulation of NK immune cells, involving both NKCC and the secretory activity, was demonstrated in newly-diagnosed GD and HT patients. This defect can be reversed by a dose-dependent treatment with DHEAS. The impairment of NK cell activity in autoimmune thyroid diseases could potentially determine a critical expansion of T/B-cell immune compartments leading to the generation of autoantibodies and to the pathogenesis of thyroid autoimmunity.

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Risk Factors Associated with Benign and Malignant Thyroid Nodules in Autoimmune Thyroid Diseases

ISRN Endocrinology ◽

10.1155/2013/673146 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Priscila Carneiro Moreira Lima ◽

Arnaldo Moura Neto ◽

Marcos Antonio Tambascia ◽

Denise Engelbrecht Zantut Wittmann

Keyword(s):

Thyroid Carcinoma ◽

Hashimoto’S Thyroiditis ◽

Thyroid Nodules ◽

Thyroid Volume ◽

Thyroid Diseases ◽

Hashimoto's Thyroiditis ◽

Graves Disease ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Demographical Data

Objectives. Assess the prevalence of thyroid nodules and predictors of malignant origin in patients with autoimmune thyroid diseases. Patients and Methods. Retrospective study including 275 patients, 198 with Graves' disease and 77 with Hashimoto’s thyroiditis. Clinical and demographical data, ultrasonographical nodule characteristics, total thyroid volume and histological characteristics were recorded. Results. Graves’ disease: the prevalence of thyroid nodules and thyroid carcinoma were 27.78% and 5.05%, respectively. Older age (OR = 1.054; 95% CI = 1.029–1.080) and larger thyroid volumes (OR = 1.013; 95% CI = 1.003–1.022) increased the chance of nodules. Younger age (OR = 1.073; 95% CI = 1.020–1.128) and larger thyroid volume (OR = 1.018; 95% CI = 1.005–1.030) predicted thyroid carcinoma. Hashimoto’s thyroiditis: the prevalence of thyroid nodules and carcinomas were 50.7% and 7.8%, respectively. Nodules were predicted by thyroid volume (OR = 1.030; 95% CI = 1.001–1.062). We found higher number of nodules in patients with thyroid carcinoma than in those with benign nodules (3 versus 2; ). Patients with Hashimoto’s thyroiditis presented nodules more frequently than patients with Graves’ disease (50.65% versus 27.28%; ), while the prevalence of carcinoma was similar (). Conclusions. Larger goiter was associated with carcinoma in Graves’ disease and Hashimoto’s thyroiditis. Younger patients presented higher risk of papillary thyroid carcinoma in Graves’ disease. The prevalence of carcinoma was similar in both conditions.

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CTLA-4 gene polymorphisms and their influence on predisposition to autoimmune thyroid diseases (Graves’ disease and Hashimoto’s thyroiditis)

Archives of Medical Science ◽

10.5114/aoms.2012.28593 ◽

2012 ◽

Vol 3 ◽

pp. 415-421 ◽

Cited By ~ 15

Author(s):

Dorota Pastuszak-Lewandoska ◽

Ewa Sewerynek ◽

Daria Domańska ◽

Aleksandra Gładyś ◽

Renata Skrzypczak ◽

...

Keyword(s):

Hashimoto’S Thyroiditis ◽

Gene Polymorphisms ◽

Thyroid Diseases ◽

Hashimoto's Thyroiditis ◽

Graves Disease ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid

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There Is No Elevation of Immunoglobulin E Levels in Albanian Patients with Autoimmune Thyroid Diseases

Journal of Thyroid Research ◽

10.1155/2014/283709 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Hatixhe Latifi-Pupovci ◽

Besa Gacaferri-Lumezi ◽

Violeta Lokaj-Berisha

Keyword(s):

Immunoglobulin E ◽

Allergic Diseases ◽

Serum Levels ◽

Thyroid Stimulating Hormone ◽

Thyroid Diseases ◽

Control Group ◽

Graves Disease ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Significant Difference

Background. Studies in several ethnic groups reported high incidence of elevated levels of immunoglobulin E (IgE) in patients with autoimmune thyroid diseases (ATD), especially in patients with Graves’ disease.Objective. To study association between serum levels of IgE and thyroid stimulating hormone receptor antibodies (TRAb) in Albanian patients with ATD.Material and Methods. Study was performed in 40 patients with Graves’ disease, 15 patients with Hashimoto’s thyroiditis, and 14 subjects in the control group. The IgE levels were measured by immunoradiometric assay, whereas the TRAb levels were measured by radioreceptor assay.Results. In all groups of subjects the IgE levels were within reference values (<200 kIU/L). Significant difference in mean concentration of IgE was found between two groups of Graves’ disease patients, and those with normal and elevated TRAb levels (22.57 versus 45.03,P<0.05). Positive correlation was found between TRAb and IgE only in Graves’ disease patients (r=0.43,P=0.006).Conclusion. In Albanian patients with ATD there is no elevation of IgE levels. This could be the result of low prevalence of allergic diseases in Albanian population determined by genetic and environmental factors.

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Pendrin Is a Novel Autoantigen Recognized by Patients with Autoimmune Thyroid Diseases

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2008-1732 ◽

2009 ◽

Vol 94 (2) ◽

pp. 442-448 ◽

Cited By ~ 21

Author(s):

Akio Yoshida ◽

Ichiro Hisatome ◽

Shinichi Taniguchi ◽

Yasuaki Shirayoshi ◽

Yasutaka Yamamoto ◽

...

Keyword(s):

Hashimoto’S Thyroiditis ◽

Sodium Iodide ◽

Chloride Transport ◽

Thyroid Diseases ◽

Tsh Receptor ◽

Hashimoto's Thyroiditis ◽

Graves Disease ◽

Sodium Iodide Symporter ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid

Abstract Context: Pendrin is an apical protein of thyroid follicular cells, responsible for the efflux of iodide into the follicular lumen via an iodide-chloride transport mechanism. It is unknown whether pendrin is recognized by autoantibodies. Objective: Our objective was to examine the prevalence of pendrin antibodies in autoimmune thyroid diseases and compare with that of thyroglobulin, thyroperoxidase, TSH receptor, and sodium iodide symporter antibodies. Design: In a prevalent case-control study, we analyzed the sera of 140 autoimmune thyroid disease cases (100 with Graves’ disease and 40 with Hashimoto’s thyroiditis) and 80 controls (50 healthy subjects, 10 patients with papillary thyroid cancer, 10 with systemic lupus erythematosus, and 10 with rheumatoid arthritis). Pendrin antibodies were measured by immunoblotting using extract of COS-7 cells transfected with pendrin and a rabbit polyclonal pendrin antibody. Results: Pendrin antibodies were found in 81% of the cases and 9% of controls (odds ratio = 44; P < 0.0001). Among cases, pendrin antibodies were more frequent and of higher titers in Hashimoto’s thyroiditis than in Graves’ disease. Pendrin antibodies correlated significantly with thyroglobulin, thyroperoxidase, and sodium iodide symporter antibodies but not with TSH receptor antibodies. Pendrin antibodies were equally effective as thyroglobulin and thyroperoxidase antibodies in diagnosis of autoimmune thyroid diseases, especially Hashimoto’s thyroiditis. Conclusions: The study identifies pendrin as a novel autoantigen recognized by patients with autoimmune thyroid diseases and proposes the use of pendrin antibodies as an accurate diagnostic tool.

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Assessment of thyroid growth stimulating activity of immunoglobulins from patients with autoimmune thyroid diseases by cytokinesis arrest assay

Acta Endocrinologica ◽

10.1530/eje.0.1360499 ◽

1997 ◽

Vol 136 (5) ◽

pp. 499-507 ◽

Cited By ~ 2

Author(s):

Shinichi Miyamoto ◽

Kanji Kasagi ◽

Mohammad Sayeedul Alam ◽

Takashi Misaki ◽

Yasuhiro Iida ◽

...

Keyword(s):

Hashimoto’S Thyroiditis ◽

Normal Subjects ◽

Thyroid Diseases ◽

Hashimoto's Thyroiditis ◽

Graves Disease ◽

Thyroid Cell ◽

Dependent Manner ◽

Autoimmune Thyroid Diseases ◽

Thyroid Cells ◽

Autoimmune Thyroid

Abstract Objective: To develop a novel bioassay for the assessment of thyroid cell growth stimulating activity using cytochalasin B (CB) and to test immunoglobulins (IgGs) from patients with autoimmune thyroid diseases. Design: The assay is based on the principle that growing cells during incubation with CB show an increased number of nuclei in a cell (N/C index), since CB. at appropriate concentrations, is known to inhibit cytoplasmic cleavage without affecting nuclear mitosis. The N/C index represents potential DNA production while cells are incubated with CB. Methods: FRTL-5 thyroid cells were incubated with various thyroid stimulators in TSH-free medium containing 2 mg/l CB for 3 days. After the incubation, the cells were harvested in trypsin/EDTA to obtain single cell suspension, fixed, dropped onto a glass slide, stained and observed under a microscope to determine the N/C index. Results: Bovine TSH at 10−3–1·0 U/l, forskolin at 1×10−7–10−5 mol/l, cholera toxin at 10×10−5–10−3 mg/l, or (Bu)2cAMP at 1× 10−5–10−3 mol/l increased the N/C index up to approximately 2·0 in a dose-dependent manner. IgGs not only from 27 patients with untreated goitrous Graves' disease but also from 14 patients with goitrous Hashimoto's thyroiditis elicited an increase in the N/C index, which exceeded the mean+2s.d. of the values for 17 normal subjects (mean ± s.d., 1·063 ±0.014). Four patients with primary myxedema displayed a normal N/C index. In Graves' disease, the N/C index did not correlate significantly with thyroid stimulating antibodies (TSAb) activities but did correlate significantly with estimated goiter size (P<0·05). IgGs containing blocking-type TSH-receptor antibodies inhibited the TSH- or Graves' IgG-stimulated increase in N/C index almost completely, but did not influence the stimulatory effect of IgG from two patients with Hashimoto's thyroiditis. Conclusions: We have developed a sensitive and simple assay for thyroid growth stimulating activity by using CB, and found that all tested patients with goitrous Graves' disease and goitrous Hashimoto's thyroiditis have thyroid growth stimulating immunoglobulins whose activity does not correlate with TSAb. European Journal of Endocrinology 136 499–507

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Altered balance of immunoregulatory T lymphocyte subsets in autoimmune thyroid diseases

Acta Endocrinologica ◽

10.1530/acta.0.1050200 ◽

1984 ◽

Vol 105 (2) ◽

pp. 200-204 ◽

Cited By ~ 10

Author(s):

Takashi Misaki ◽

Junji Konishi ◽

Yasuhiro Iida ◽

Keigo Endo ◽

Kanji Torizuka

Keyword(s):

T Cells ◽

T Lymphocytes ◽

Hashimoto’S Thyroiditis ◽

Mononuclear Cells ◽

Cytotoxic T Cells ◽

Hashimoto's Thyroiditis ◽

Graves Disease ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Significant Difference

Abstract. Three monoclonal antibodies recognizing cell surface antigens of total peripheral (OKT3), helper/inducer (OKT4) and suppressor/cytotoxic (OKT8) T lymphocytes were used by an indirect immunofluorescence technique to enumerate peripheral T lymphocytes in 25 patients with Graves' disease (including 4 euthyroid Graves' patients), 16 patients with Hashimoto's thyroiditis and 22 normal controls. Total lymphocyte count and percentages of overall T and helper/inducer T cells among peripheral lymphocytes in these conditions showed no significant difference from those of the controls. Percentage of suppressor/cytotoxic T cells, however, was decreased in Graves' disease patients with or without hyperthyroidism. The ratio of helper/inducer T cells to suppressor/cytotoxic T cells was increased in Graves' disease population and slightly increased in hypothyroid Hashimoto's thyroiditis patients. The ratio correlated with the mitogenic response of peripheral mononuclear cells to phytohaemagglutinin, but not with the serum levels of thyroid hormones nor with the titres of thyroid autoantibodies. These findings are in accordance with the results of previous functional studies and indicate possible defects in suppressor T lymphocytes in autoimmune thyroid disease.

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The role of apoptosis in development of autoimmune thyroid diseases

Bulletin of Siberian Medicine ◽

10.20538/1682-0363-2009-1-64-70 ◽

2009 ◽

Vol 8 (1) ◽

pp. 64-70

Author(s):

Yu. V. Nedosekova ◽

O. I. Urasova ◽

Ye. B. Kravets ◽

A. V. Chaikovsky

Keyword(s):

Thyroid Gland ◽

Hashimoto’S Thyroiditis ◽

Thyroid Diseases ◽

Hashimoto's Thyroiditis ◽

Graves Disease ◽

Autoimmune Thyroid Diseases ◽

Autoimmune Thyroid ◽

Immunological Abnormalities ◽

Apoptotic Factors

In the review representations about a role apoptosis by autoimmune thyroid diseases, such as Graves' disease and Hashimoto's thyroiditis, the basic pathogenetic links immunological abnormalities at the these diseases have been discussed. At has been demonstrated changes in a thyroid gland, and also changes endocellular pro- and anti-apoptotic factors are shown at Hashimoto's thyroiditis and Graves' disease.

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