Increased circulating follicular regulatory T cells in Hashimoto’s thyroiditis

Abstract

Objective: Follicular T helper (Tfh) cells are involved in the pathogenesis of Hashimoto's thyroiditis (HT), while follicular T regulatory (Tfr) cells inhibit Tfh cells, which mediate B cell responses. However, the role of Tfr cells in HT remains unclear.

Methods: Forty-six healthy controls (HCs) and 84 HT patients were enrolled in the study. The percentage of Treg cells, CXCR5^? Treg cells, and Tfr cells; the Tfr/Tfh ratio; and the percentage of ICOS, PD-1, CTLA-4, CXCR3 and CCR6 in Tfr cells were investigated; furthermore, the associations between the percentage of Tfr cells or the Tfr/Tfh ratio and the autoantibody indices were investigated.

Results: Compared with that in the HCs, the percentage of Treg cells in the HT patients was not significantly changed, but the percentage of CXCR5^? Tfr cells was decreased. In contrast, both the percentage of Tfr cells and the Tfr/Tfh ratio were significantly increased in the HT patients. Among the Tfr cells, the percentage of Th2-like Tfr cells was increased in the HT patients, while the percentage of Th17-like Tfr cells was decreased. Moreover, the percentages of ICOS and PD-1 on Tfr cells were significantly increased in the HT patients, while the percentage of CTLA-4 on Tfr cells was significantly decreased. However, the percentage of ICOS, PD-1 and CTLA-4 on Treg or CXCR5^? Treg cells was not significantly changed. Last, no association was found between either the percentage of Tfr cells or the Tfr/Tfh ratio and the antithyroglobulin and antithyroid peroxidase antibody levels in the HT patients.

Conclusions: In the HT patients, the circulating Tfr cell percentage and Tfr/Tfh ratio were significantly increased, but the humoral immune function of Tfr cells might be impaired.     

Role of Different CD40 Polymorphisms in Graves’ Disease and Hashimoto’s Thyroiditis

Genome-wide association studies have led to the discovery of several susceptibility genes related to autoimmune thyroid diseases (AITDs). However, controversial results have been reported regarding the role of single-nucleotide polymorphism (SNP) of CD40 in the disease susceptibility. The objective of this study was to identify the relationship of the polymorphisms of three sites of CD40 with the susceptibility to AITD in the Chinese population. We genotyped three polymorphisms of CD40: C/T ?1 SNP, 58038T site of the third exon and C64610G site of the ninth exon in 196 GD cases, 121 HT cases and 122 control subjects. The three putative polymorphism sites were amplified by PCR for sequencing and analysis. The genotype frequencies of CD40 ?1 C/C genotype and C allele were significantly higher in the GD group than those in normal control. For the C64610G polymorphism, the C/G genotype was significantly more frequent in HT group than in control group, and the G allele frequencies in the GD and HT group were both higher than those in control group. These results indicated that there exist different susceptibility loci for AITD within CD40, each contributing a different effect in the onset and development of AITDs.     

Critical amino acid variants in HLA-DRB1 allotypes in the development of Graves’ disease and Hashimoto’s thyroiditis in the Japanese population

The effects of amino acid variants encoded by human leukocyte antigen (HLA) class II on the development of Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) have not been fully elucidated. We investigated the HLA-DRB1 genes of 243 GD patients and 82 HT patients in the Japanese population and compared the frequencies of HLA-DRB1 alleles and HLA-DRB1 amino acid variants between these patients and the Japanese populations previously reported by another institution. The frequencies of HLA-DRB1*04:05 and -DRB1*14:03 alleles were significantly higher and those of HLA-DRB1*01:01 and -DRB1*15:02 alleles were lower in GD patients than in controls. The frequencies of HLA-DRB1*08:03 and -DRB1*09:01 alleles were significantly higher and that of the HLA-DRB1*13:02 allele was lower in HT patients than in controls. A blind association analysis with all amino acid positions identified DRß9 and DRß31 for GD and DRß9, DRß13, and DRß21 for HT. The frequency of Glu-9 was significantly higher and that of Cys-9 was lower in GD patients than in controls. The frequencies of Lys-9 and Phe-13 were significantly higher in HT patients than in controls. DRß9 and DRß13 could be critical amino acid positions in the development of GD and HT.     

Determinants of thyroid autoantibody production in Hashimoto’s thyroiditis

Hashimoto’s thyroiditis (HT) is the most prevalent thyroid autoimmune disorder, characterized by the presence of specific thyroid autoantibodies (TAb). The development of autoimmunity, including TAb production and clinical presentation of HT, is determined by a complex interplay of genetic susceptibility and several endogenous and environmental factors, which are discussed in this article. During the progression of the disease, TAb production precedes clinical manifestations, although the correlation between TAb concentrations and thyroid function is weak. We do not treat euthyroid HT patients despite elevated TAb; while in hypothyroidism, replacement therapy with l-thyroxine is required. Until now, an effective approach to prevent TAb production and the development of clinical disease has not yet been established. However, further identification of risk factors and their interaction may help in the prevention of thyroid autoimmunity.     

Therapeutic effect of mesenchymal stem cell on Hashimoto’s thyroiditis in a rat model by modulating Th17/Treg cell balance

Abstract

The autoimmune condition Hashimoto’s thyroiditis (HT) is a disease wherein lymphocytes mediate the autoimmune damage and destruction of the thyroid gland. There are currently no effective means of treating HT, with the primary strategies of thyroid hormone therapy, surgery, or immunomodulatory therapy being associated with serious risks and side effects. There is thus a clear and urgent need to identify novel treatments for HT. In this study, we utilize female SD rats induced HT to evaluated the ability of transplanted MSCs to regulate Th17/Treg interactions in a rat Hashimoto’s thyroiditis (HT) model system. The results showed that Rats in the HT model group exhibited increased thyroid autoantibody levels consistent with successful model development, whereas these levels were lower in rats treated with MSCs. There were also fewer thyroid lesions and less lymphoid infiltration of the thyroid in MSC-treated rats relative to HT model rats, as well as fewer Th17 cells and more Treg cells – an observation consistent with the cytokine analyses. All of these showed that MSCs can regulate Th17/Treg interactions in a rat Hashimoto’s thyroiditis (HT) model system. It suggested that transplanted MSCs could be a potential immunotherapy strategy for the treatment of Hashimoto’s thyroiditis.     

Frequency and Distribution of DNA fragmentation in Hashimoto’s thyroiditis and development of papillary thyroid carcinoma

Downregulation of apoptosis and high expression of bcl-2 play an important role in the development of follicular lymphoma. However, little is known about apoptosis in thyroid disease, particularly with respect to the development of papillary carcinoma from Hashimoto’s thyroiditis. To study the early stages of cell death in various types of thyroid disease, surgical specimens from 31 patients including Hashimoto’s thyroiditis (HT,n=7), papillary carcinoma (PC,n=12), Hashimoto’s thyroiditis with papillary carcinoma (HTPC,n=5), and Graves’ disease (GD,n=7) were examined by anin situ nucleotidyl transferase assay (ISNTA), which detects DNA fragmentation. Control normal thyroid tissue (NT,n=7) was obtained from surgically resected papillary thyroid carcinomas sampled away from the primary tumor. An immunohistochemical (IHC) method was used to detect bcl-2 expression. Positive ISNTA nuclei in thyroid follicular cells or tumor cells per section were counted in all parenchymal areas, excluding areas of lymphocyte aggregates. The intensity of bcl-2 staining was graded on a scale of 1+ to 3+. The number of ISNTA-positive thyroid follicular cells was a significantly higher in HT compared to GD. In addition, there was significantly lower number of ISNTA positive non-neoplastic thyroid follicular cells in HTPC compared to HT alone. Strong expression of bcl-2 was found in all cases of GD and NT, but much less bcl-2 staining was seen in HT. There was moderate expression of bcl-2 in HTPC and PC. These findings suggest that (1) DNA fragmentation of the thyroid follicular cells plays an important role in the thyroid injury in HT but not in GD, (2) expression of bcl-2 may overcome the apoptosis in GD but not in HT, and (3) downregulation of DNA fragmentation of the follicular cells in Hashimoto’s thyroiditis associated with papillary carcinoma may suggest an important mechanism for tumor pathogenesis.     

Genistein improves thyroid function in Hashimoto’s thyroiditis patients through regulating Th1 cytokines

Hashimoto thyroiditis (HT) is a common autoimmune disease. Genistein is an isoflavone with immunomodulatory functions in various diseases. In this double-blind, randomized, placebo-controlled clinical study, we investigated the effects of genistein on patients with HT. A total of 218 patients were recruited. Genistein treated patients had a significant increased T₄, fT₄ levels, as well as reduction in serum TSH, TPOAb and TgAb levels, compared with those receiving placebo. Furthermore, Th1 related cytokine IFN-γ and IL-2 changes after genistein treatment suggest the immune modulating effect of genistein is mediated through regulating the function of Th1 cells. Overall, the genistein administration was effective and well tolerated in HT patients. These results demonstrate an immunological effect of genistein on HT patients. Further studies are warranted to determine the longer-term effects and possible chemopreventive effects on thyroid cancer in HT patients.     

Increased circulating Tfh17 and PD-1+Tfh cells are associated with autoantibodies in Hashimoto’s thyroiditis

Abstract

Objective: Hashimoto’s thyroiditis (HT) is characterized by autoantibodies targeting the thyroid. Abnormal CD4⁺CXCR5⁺T cell levels were previously shown to be associated with HT. However, Tfh cells consist of heterogeneous subpopulations, and which T follicular helper (Tfh) cell subpopulation participates in the pathogenesis of HT remains poorly understood.

Methods: Thirty healthy controls (HCs) and 52 HT patients were enrolled in the study. The percentages of Tfh, ICOS⁺Tfh, PD1⁺Tfh, Tfh1, Tfh2, Tfh17, effector Tfh, resting Tfh, effector memory Tfh, central memory Tfh, and naïve Tfh cells in the peripheral blood were all determined via flow cytometry, and the associations between the percentages of these cells and thyroid function indices were also investigated.

Results: The percentage of Tfh cells was significantly higher in HT patients than in HCs. Examination of the Tfh cell subsets revealed that the percentages of Tfh1, Tfh2, and resting Tfh cells were significantly decreased, while those of the ICOS⁺Tfh, PD1⁺Tfh, Tfh17, and effector Tfh cells were significantly increased in HT patients. No significant differences in effector memory, central memory or naïve Tfh cell percentages were noted between the HC and HT groups. Furthermore, the percentage of PD1⁺Tfh cells was positively correlated with anti-thyroglobulin antibody levels. Most importantly, only Tfh17 cell percentages were positively correlated with anti-thyroglobulin and anti-thyroid peroxidase antibody levels and were negatively correlated serum free T3 and free T4 levels in HT patients.

Conclusions: Increased circulating Tfh17 cell and PD1⁺Tfh percentages are associated with higher autoantibody levels in HT patients, which imply that Tfh17 or PD1⁺Tfh cells may play a pathogenic role in the development of HT.     

Maltoma of the thyroid and Sjögren’s syndrome in a woman with Hashimoto’s thyroiditis

We report the case of a 70-yr-old woman with maltoma of the thyroid, Sjögren’s syndrome, and a history of Hashimoto’s thyroiditis. The patient underwent a total thyroidectomy for a recently growing mass of the thyroid, while being treated with l-thyroxine for Hashimoto’s thyroiditis. Postoperatively, routine histologic examination was consistent with the diagnosis of chronic lymphocytic thyroiditis of autoimmune etiology. Three years later, the patient presented with high temperature, anorexia, and coughing. This time, a microscopic examination of deeper thyroid tissue sections and an immunohistochemical study revealed a low-grade, non-Hodgkin lymphoma, MALT type. Simultaneously, the diagnosis of Sjögren’s syndrome was established and the patient is currently under investigation for generalized lymphoma. This case clearly demonstrates the difficulty in differentially diagnosing Hashimoto’s thyroiditis from low-grade MALT lymphoma by the use of routine histologic examination.     

Haemangiopericytoma of the thyroid gland in combination with Hashimoto’s disease

We present a hitherto unique case of haemangiopericytoma (HP) of the thyroid gland in a 15-year-old female patient suffering from Hashimotos disease for several months. Since angiogenesis has been discussed to play a major role in both diseases, we examined the expression of vascular endothelial growth factor (VEGF), VEGF receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). Most interestingly, strong expression of PDGFR and was found in spindle-shaped tumour cells and tumour vessels in HP, while VEGF and VEGFR type I and -II were negative in these regions. In contrast, VEGF was expressed in the lymphoid infiltrate of Hashimotos disease. Since PDGFR- is commonly expressed in pericytes, we suggest that the strong expression discovered in this study further supports the view that HP is derived from pericytes. The combination of HP and Hashimotos disease is most probably a coincidental event. However, this case confirms previous reports demonstrating that in patients with Hashimotos disease different neoplasias can occur.     

Methylation levels of the TNFA gene are different between Graves’ and Hashimoto’s diseases and influenced by the TNFA polymorphism

Graves’ disease (GD) and Hashimoto’s disease (HD) are different pathological types of autoimmune thyroid diseases (AITDs). However, the epigenetic differences between these diseases have not been elucidated. DNA methylation is one of the primary epigenetic modifications that reflect environmental influences on gene expression. In this study, we evaluated the methylation status of six CpG sites in the TNFA promoter using pyrosequencing and analyzed the data in combination with functional polymorphisms (?1031?T/C and?+123?C/T) in the TNFA gene to clarify the role of gene methylation on the prognosis of AITDs. We examined the methylation pattern in 52 patients with GD, 60 patients with HD, and 29 healthy controls by pyrosequencing. Additionally, we also genotyped the polymorphisms from 163 patients with GD, 152 patients with HD, and 94 healthy controls using the restriction fragment length polymorphism (RFLP) method. Each proportion of subjects with low methylation of the ?72 CpG site (≤11.9%), low methylation of the ?49 CpG site (≤15.5%), and low methylation of the ?38 CpG site (≤8.9%) was significantly increased in the groups with high concentration of TNF-α (≥0.134?pg/mL). The methylation level of the ?72 CpG site was significantly higher in GD cases (10.7?±?4.9%) than in healthy controls (6.8?±?3.9%). The methylation level of the ?49 and ?38 CpG sites were significantly higher in patients with GD in remission (20.5?±?9.5%, 17.6?±?8.0%, respectively) than in healthy controls (13.0?±?7.6%, 7.9?±?7.3%, respectively). The frequency of the TNFA???1031C carrier (CT?+?CC) is correlated with higher TNF-α production and was significantly higher in GD (35.0%) and HD (39.5%) cases than in controls (19.1%). In the subjects with the TNFA???1031C carrier (CT?+?CC), the methylation level of the ?72 CpG site was significantly higher in GD (11.5?±?5.7%) than in HD (6.0?±?3.4%). However, there was no difference between GD and HD in patients with the TT genotype. Cumulatively, our data indicate the methylation levels of CpG sites in the TNFA gene may be related to the difference between GD and HD in AITDs and may be influenced by the TNFA gene polymorphism.     

Hashimoto’s thyroiditis: TGAb,TPOAb, TRAb and recovery from hypothyroidism

Hashimoto described four patients with goiter. The histology of the goiter was characterized by diffuse lymphocytic infiltration, fibrosis and epithelial cell destruction. Thyroglobulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb) have been used to diagnose Hashimoto’s thyroiditis. Patients with positive TGAb and/or TPOAb have been assumed to have Hashimoto’s thyroiditis. Approximately 10% of those with positive TGAb and/or TPOAb have hypothyroidism. There are two types of autoimmune thyroiditis: goitrous Hashimoto’s thyroiditis and atrophic thyroiditis. The latter patients have blocking antibody (thyroid-stimulating hormone [TSH]-stimulation blocking antibody [TSBAb]). TSBAb is a TSH-receptor antibody (TRAb). TSBAb causes thyroid atrophy and hypothyroidism. TGAb and/or TPOAb do not necessarily cause hypothyroidism. Hypothyroid patients with Hashimoto’s thyroiditis usually receive life-long l-thyroxine therapy. However, spontaneous recovery from hypothyroidism has been reported. Patients who had Hashimoto’s hypothyroidism and then Graves’ hyperthyroidism (and vice versa), have also been reported. Hashimoto’s hypothyroidism and Graves’ hyperthyroidism could be the opposite spectrums of one disease.     

Microarray profiling and functional analysis reveal the regulatory role of differentially expressed plasma circular RNAs in Hashimoto’s thyroiditis

Immunologic Research - Circular RNAs (circRNAs) have been revealed as being abundantly expressed in a variety of tissues and have been found to contribute to the regulation of many autoimmune...     

Oxidative stress and regulated cell death in Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. Motor deficits usually associated with PD correlate with dopaminergic axonal neurodegeneration starting at the striatum, which is then followed by dopaminergic neuronal death in the substantia nigra pars compacta (SN), with both events occurring already at the prodromal stage.We will overview the main physiological characteristics responsible for the higher susceptibility of the nigrostriatal circuit to mitochondrial dysfunction and oxidative stress, as hinted by the acting mechanisms of the PD-causing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Then, we will present multiple lines of evidence linking several cell death mechanisms involving mitochondria and production of reactive oxygen species to neuronal loss in PD, namely intrinsic and extrinsic apoptosis, necroptosis, ferroptosis, parthanatos and mitochondrial permeability transition-driven necrosis. We will focus on gathered data from postmortem PD samples and relevant in vivo models, especially MPTP-based models.     

Time of transplantation and cell preparation determine neural stem cell survival in a mouse model of Huntington’s disease

Cell replacement therapies for neurodegenerative diseases, using multipotent neural stem cells (NSCs), require above all, a good survival of the graft. In this study, we unilaterally injected quinolinic acid (QA) into the striatum of adult mice and transplanted syngeneic NSCs of enhanced green fluorescent protein-transgenic mice into the lesioned striatum. The injection of QA leads to an excitotoxic lesion with selective cell death of the medium sized spiny neurons, the same cells that are affected in Huntington’s disease. In order to investigate the best timing of transplantation for the survival of donor cells, we transplanted the stem cells at 2, 7 and 14 days after injury. In addition, the influence of graft preparation prior to transplantation, i.e., intact neurospheres versus dissociated cell suspension on graft survival was investigated. By far the best survival was found with the combination of early transplantation (i.e., 2 days after QA-lesion) with the use of neurospheres instead of dissociated cell suspension. This might be due to the different states of host’s astrocytic and microglia activation which we found to be moderate at 2, but pronounced at 7 and 14 days after QA-lesion. We also investigated brain derived neurotrophic factor (BDNF)-expression in the striatum after QA-lesion and found no significant change in BDNF protein-level. We conclude that already the method of graft preparation of NSCs for transplantation, as well as the timing of the transplantation procedure strongly affects the survival of the donor cells when grafted into the QA-lesioned striatum of adult mice.     

Coordination of grasping and walking in Parkinson’s disease

Studies on grasp control underlying manual dexterity in people with Parkinson disease (PD) suggest that anticipatory grasp control is mainly unaffected during discrete tasks using simple two-digit grasp. Nevertheless, impaired hand function during daily activities is one of the most disabling symptoms of PD. As many daily grasping activities occur during functional movements involving the whole body, impairments in anticipatory grasp control might emerge during a continuous dynamic task such as object transport during walking. In this case, grasp control must be coordinated along with multiple body segments. The present study investigated the effect of PD on anticipatory grasp control and intersegmental coordination during walking with a hand-held object. Nine individuals with idiopathic PD (tested OFF and ON medication) and nine healthy age-matched controls carried a grip instrument between their right thumb and index finger during self-paced and fast walking. Although the amplitude of grip forces was higher in standing and walking for subjects with PD, both subjects with PD and control subjects coupled grip and inertial force changes in an anticipatory fashion while walking. However, gait-induced motions of the object relative to that of the trunk (i.e., dampening) was reduced in subjects with PD. Medication increased the dampening in all subjects with PD. We suggest that these differences are associated with impairments in intersegmental coordination.     

Circulating levels of IL-1 family cytokines and receptors in Alzheimer’s disease: new markers of disease progression?

Background

Although the mechanisms underlying AD neurodegeneration are not fully understood, it is now recognised that inflammation could play a crucial role in the initiation and progression of AD neurodegeneration. A neuro-inflammatory network, based on the anomalous activation of microglial cells, includes the production of a number of inflammatory cytokines both locally and systemically. These may serve as diagnostic markers or therapeutic targets for AD neurodegeneration.

Methods

We have measured the levels of the inflammation-related cytokines and receptors of the IL-1 family in serum of subjects with AD, compared to mild cognitive impairment (MCI), subjective memory complaints (SMC), and normal healthy subjects (NHS). Using a custom-made multiplex ELISA array, we examined ten factors of the IL-1 family, the inflammation-related cytokines IL-1α, IL-1β, IL-18, and IL-33, the natural inhibitors IL-1Ra and IL-18BP, and the soluble receptors sIL-1R1, sIL-1R2, sIL-1R3, and sIL-1R4.

Results

The inflammatory cytokines IL-1α and IL-1β, their antagonist IL-1Ra, and their soluble receptor sIL-1R1 were increased in AD. The decoy IL-1 receptor sIL-1R2 was only increased in MCI. IL-33 and its soluble receptor sIL-1R4 were also significantly higher in AD. The soluble form of the accessory receptor for both IL-1 and IL-33 receptor complexes, sIL-1R3, was increased in SMC and even more in AD. Total IL-18 levels were unchanged, whereas the inhibitor IL-18BP was significantly reduced in MCI and SMC, and highly increased in AD. The levels of free IL-18 were significantly higher in MCI.

Conclusions

AD is characterised by a significant alteration in the circulating levels of the cytokines and receptors of the IL-1 family. The elevation of sIL-1R4 in AD is in agreement with findings in other diseases and can be considered a marker of ongoing inflammation. Increased levels of IL-1Ra, sIL-1R1, sIL-1R4, and IL-18BP distinguished AD from MCI and SMC, and from other inflammatory diseases. Importantly, sIL-1R1, sIL-1R3, sIL-1R4, and IL-18BP negatively correlated with cognitive impairment. A significant elevation of circulating sIL-1R2 and free IL-18, not present in SMC, is characteristic of MCI and disappears in AD, making them additional interesting markers for evaluating progression from MCI to AD.

     

Suspension culture of Marek’s disease virus and evaluation of its immunological effects

Marek’s disease virus (MDV) is a cell-associated α-herpesvirus of chickens. It is difficult to grow MDV in suspension culture. Therefore, MDV vaccines are currently produced using adherent primary chicken embryo fibroblasts, and on a large scale this is labour-intensive and costly. In this study, the CVI988 strain of MDV was inoculated into chicken fibroblast cell line UMNSAH/DF-1 (DF-1) cultured by microcarrier suspension for the proliferation experiment. Moreover, the effects of culture conditions, such as inoculation method, multiplicity of infection (MOI), microcarrier concentration, and pH value, on the proliferation of MDV were investigated. The results demonstrated that the maximum viral load of 64.76?±?2.64?×?10⁶ PFU/flask in a working volume of 100?ml could be obtained using synchronous cell seeding and inoculation method at an MOI of 0.02 and a microcarrier concentration of 5?g/l at pH 7.2. At the same time, the CVI988/DF-1 vaccines prepared by the microcarrier culture process and the traditional adherent cell culture process (CVI988/Rispens) were compared through bird experiments. We found a protective rate of 94.4% using the CVI988/DF-1 vaccine with specific pathogen-free chickens that was equivalent to that of the commercial vaccine CVI988/Rispens (protection rate of 94.1%). In this study, the MDV CVI988/DF-1 vaccine prepared by the microcarrier suspension culture of DF-1 cells could provide effective immune protection for specific pathogen-free chickens, providing a reference for the prevention and control of MD and further development of a large-scale bioreactor for producing the MD vaccine.     

Association of established thyroid peroxidase autoantibody (TPOAb) genetic variants with Hashimoto’s thyroiditis

Hashimoto's thyroiditis (HT) is the most common form of autoimmune thyroid diseases (AITD) characterized by progressive destruction of thyroid tissue that may lead to hypothyroidism. High thyroid autoantibodies against thyroid peroxidase (TPOAb) levels are present in 90% of patients with HT and serve as a clinical marker for the detection of early AITD/HT. The main aim of our study was to test whether recently identified genetic variants associated with TPOAb are also involved in HT development.

A total of 504 unrelated individuals, including 200 patients with HT and 304 controls, were involved in this study. Diagnosis of HT cases was based on clinical examination, measurement of thyroid hormones (TSH and fT4) and antibodies (TgAb, TPOAb) and ultrasound examination. We selected and genotyped 14 known TPOAb-associated genetic variants. Case–control logistic regression model was used to test the association of selected genetic variants with HT. Additionally, we tested association of the same genetic variants with thyroid related quantitative traits (TPOAb levels, TgAb levels and thyroid gland volume) using linear regression.

Three genetic variants showed nominal association with HT; rs10774625 in ATXN2 gene (p?=?0.0149, OR?=?0.73, CI?=?0.56–0.94), rs7171171 near RASGRP1 gene (p?=?0.0356, OR?=?1.4, CI?=?1.02–1.92) and rs11675434 in TPO gene (p?=?0.041, OR?=?1.31, CI?=?1.01–1.69). Two of these SNPs (rs1077462, rs11675434) also showed association with TPOAb levels (p?=?0.043, β?=??0.39; p?=?0.042, β?=?0.40, respectively) and one (rs7171171) was associated with thyroid gland volume (p?=?0.0226, β?=??0.21).

Our findings suggest that variants inside or near TPO, ATXN2 and RASGRP1 genes are associated with HT. Identified loci are novel to HT and represent good basis for further exploration of HT susceptibility.