The role of nuclear factor-kappaB in the development of autoimmune diseases: a link between genes and environment.

Although autoimmune diseases are relatively common, mechanisms that lead to their development remain largely unknown. Nuclear factor-kappaB (NF-kappaB), as a key transcription factor involved in the regulation of immune responses and apoptosis, appears to be a good candidate for studies on the pathogenesis of autoimmunity. This review presents how perturbations of the NF-kappaB signaling pathway may contribute to self-tolerance failure, initiation of autoimmune inflammatory response as well as its persistent maintenance and therefore to the development of common autoimmune diseases including rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus, thyroid autoimmune diseases, systemic lupus erythematosus as well as inflammatory bowel diseases and psoriasis. A special emphasis is put on the genetic variations in the NF-kappaB related genes and their possible association with susceptibility to autoimmune diseases, as well as on the therapeutic potential of the NF-kappaB targeted strategies in the treatment of autoimmunity.

Guidelines of Polish National Societies Diagnostics and Treatment of Thyroid Carcinoma. 2018 Update.

Significant advances have been made in thyroid can-cer research in recent years, therefore relevant clinical guidelines need to be updated. The current Polish guidelines "Diagnostics and Treatment of Thyroid Carcinoma" have been formulated at the "Thyroid Cancer and Other Malignancies of Endocrine Glands" conference held in Wisla in November 2015 [1].

[The influence of vitamin D deficiency on cancers and autoimmune diseases development]. / Wplyw niedoboru witaminy D na rozwój nowotworów i chorób autoimmunologicznych.

There is a growing number of diseases which prevalence can be associated with vitamin D deficiency. The link between low cholecalciferol concentration and bone diseases is well established, however there is also data suggesting that it may influence development and progression of different cancers and autoimmune diseases. The in vitro studies proved that the active vitamin D metabolite--1,25(OH)(2)D(3) may arrest the cell cycle progression, induce apoptosis as well as regulate T cells and antigen presenting cells function. Results of the in vivo experiments suggest that vitamin D deficiency accelerates development of autoimmune diseases and cancers in animals. Epidemiological studies imply that the vitamin D deficiency is also associated with the increased incidence of autoimmune diseases and cancers in people. The main determinant of vitamin D serum concentration in a human body is skin synthesis. The changes in the lifestyle, air pollution as well as a common use of sun screens caused that the contemporary European receives little sunlight compared to his ancestors. According to the recent epidemiological studies, the vitamin D concentrations in serum of people who live in high latitudes (above 34 degrees N/S), including Poland, is far from being sufficient. This paper reviews results of the recent studies concerning the potential role of the vitamin D in the development of cancers and autoimmune diseases, as well as provides guidelines for vitamin D supplementation.

Interaction of HLA-DRB1 alleles with CTLA-4 in the predisposition to Graves' disease: the impact of DRB1*07.

OBJECTIVE: To study interactions between the two most widely confirmed Graves' disease (GD) loci: HLA-DRB1 and CTLA-4. HLA-DRB1*03 (risk allele) and DRB1*07 (protective allele) were analyzed in this aspect, the linked TNF G(-308)A polymorphism was also considered. DESIGN: A case-control study of 429 patients with GD compared to 308 healthy subjects. The impact of genes and their interactions were analyzed by stepwise logistic regression. RESULTS: The independent effects of DRB1*03 and DRB1*07 were confirmed in our study both by stratification studies and logistic regression. CTLA-4 did not appear to be associated with GD when the interactions with other genes were considered. By logistic regression we observed a significant interaction between DRB1*07 and CTLA-4 and revealed that CTLA-4 49G attenuated the DRB1*07-related protection, the effect noticed also in three-way stratification studies. We confirmed that the TNF G(-308)A polymorphism is only a marker of the DRB1 status. CONCLUSION: Our results stress the importance of complex gene interactions in the multigene predisposition to GD. The interactions between two predisposing loci, DRB1 and CTLA-4, are exerted rather by DRB1*07 than DRB1*03 allele: CTLA-4 acts via switching off the protective DRB1*07 influence, whereas the effect of DRB1*03 is independent.

[Correlation between thyroid stimulating immunoglobulins and thyrotropin binding inhibitory immunoglobulins levels in patients with Graves' disease]. / Badanie korelacji pomiedzy poziomami przeciwcial stymulujacych tarczyce i przeciwcial blokujacych wiazanie tyreotropiny na receptorze TSH u chorych z choroba Gravesa-Basedowa.

INTRODUCTION: The II generation method using human recombination thyrotropin receptors for measurement of thyrotropin binding inhibitory immunoglobulins (TBII) is characterized by increased sensitivity and specificity in comparison with I generation method. AIM OF STUDY was to determine, whether TBII levels measured with II generation assay reflect thyroid stimulation and whether measurement of thyroid stimulating antibodies (TSI) could be replaced by TBII determinations. Specific aim was to evaluate, whether correlation between TSI and TBII levels is stable during antithyroid therapy. MATERIAL AND METHODS: 41 patients with the newly diagnosed Graves' disease were included in the study. TSI (cAMP levels in CHO cell line) and TBII (II generation assay) levels were determined before treatment and after 1, 3, 6, 9 and 12 months of thiamazol therapy. Moreover, thyroid blocking antibodies were determined after 12 months of treatment. RESULTS: 32 patients (82.05%) had positive basic TSI level and 35 patients (89.74%) had positive basic TBII level. After 12 months of therapy negative level of TSI was observed in 67.57% of patients and negative level of TBII was founded in 45.85% of patients. Correlation between TSI and TBII levels was positive during treatment course except time after 9 months of therapy. CONCLUSIONS: TBII level is adequate parameter to assess thyroid stimulation intensity. Positive correlation between TSI and TBII levels is present during almost whole treatment course. TBII seems to be reliable parameter in disease activity monitoring and response to therapy.

Predicting a relapse of Graves' hyperthyroidism in adults during the early phase of treatment with anti-thyroid drugs.

INTRODUCTION: The long-term effectiveness of anti-thyroid drugs (ATD) in the treatment of Graves' hyperthyroidism (GH) is still unsatisfactory and difficult to predict. The aim of this study was to evaluate the usefulness of a determination of serum level of thyrotropin-binding inhibiting immunoglobulins (second generation TBII assay) in predicting the possibility of relapse in the early phase of pharmacological treatment. MATERIAL AND METHODS: We investigated 37 patients within the 20-60 age range with the first occurrence of GH. All patients were treated with thiamazole for 12 months. Clinical assessment, ultrasound estimation of thyroid volume and determination of serum thyrotropin, free thyroxine, free triiodothyronine, thyroid autoantibodies and TBII levels were carried out at the onset and after 1, 3, 6, 9 and 12 months of ATD treatment. RESULTS: The mean follow-up period after ATD withdrawal was 27.24 +/- 5.81 months. Of 37 patients 12 (32%) had a relapse of hyperthyroidism (mean time 8.17 +/- 6.91 months after drug withdrawal). The difference in TBII levels between the relapse and the remission group was found to be significant after the first month of therapy until the end of ATD treatment. We observed that patients with TBII above 14 IU/L after 3 months and above 8 IU/L after 6 months of therapy relapsed more frequently than patients with lower levels (sensitivity 50% and specificity 92 and 96%, respectively). CONCLUSIONS: The study confirmed that TBII estimation in the early phase of ATD could be useful in the proper planning of GH therapy and early qualification to more radical treatment (radioiodine or surgery).

Diagnostics and Treatment of Thyroid Carcinoma.

Revised Guidelines of Polish National Societies Prepared on the initiative of the Polish Group for Endocrine Tumours approved in their final version between November 16th and 28th, 2015 by the Scientific Committee of the V Conference "Thyroid Cancer and other malignancies of endocrine glands" organised between November 14th and 17th, 2015 in Wisla, Poland; called by the following Societies: Polish Endocrine Society, Polish Society of Oncology, Polish Thyroid Association, Polish Society of Pathologists, Society of Polish Surgeons, Polish Society of Surgical Oncology, Polish Society of Clinical Oncology, Polish Society of Radiation Oncology, Polish Society of Nuclear Medicine, Polish Society of Paediatric Endocrinology, Polish Society of Paediatric Surgeons, Polish Society of Ultrasonography Gliwice-Wisla, 2015 DECLARATION: These recommendations are created by the group of delegates of the National Societies, which declare their willingness to participate in the preparation of the revised version of the Polish Guidelines. The members of the Working Group have been chosen from the specialists involved in medical care of patients with thyroid carcinoma. Directly before the preparation of the Polish national recommendations the American Thyroid Association (ATA) published its own guidelines together with a wide comment fulfilling evidence-based medicine (EBM) criteria. ATA Guidelines are consistent with National Comprehensive Cancer Network (NCCN) Recommendation. According to the members of the Working Group, it is necessary to adapt them to both the specific Polish epidemiological situation as well as to the rules referring to the Polish health system. Therefore, the Polish recommendations constitute a consensus of the experts' group, based on ATA information. The experts analysed previous Polish Guidelines, published in 2010, and other available data, and after discussion summed up the results in the form of these guidelines. It should be added that Part II, which constitutes a pathological part, has been available at the website of the Polish Society of Pathologists for acceptance of the members of the Society, and no essential comments have been proposed. The Members of the Group decided that a subgroup elected from among them would update the Guidelines, according to EBM rules, every year. The Revised Guidelines should help physicians to make reasonable choices in their daily practice; however, the final decision concerning an individual patient should be made by the caring physician responsible for treatment, or optimally by a therapeutic tumour board together with the patient, and should take into consideration the patient's health condition. It should be emphasised that the recommendations may not constitute a strict standard of clinical management imposed on medical staff. The data from clinical trials concerning numerous clinical situations are scarce. In such moments the opinion of the management may differ from the recommendations after considering possible benefits and disadvantages for the patient.

Disturbed expression of type 1 and type 2 iodothyronine deiodinase as well as titf1/nkx2-1 and pax-8 transcription factor genes in papillary thyroid cancer.

Type 1 and type 2 iodothyronine 5' deiodinases (D1 and D2, respectively) catalyze the conversion of thyroxine (T(4)) to triiodothyronine (T(3)). Similar to other genes crucial for T(3) generation, D1 and D2 expression might be disturbed in papillary thyroid cancer (PTC) possible as a result of impairments in thyroid transcription factors Titf1/Nkx2-1 and Pax-8. The aim of the study was to investigate changes in the expression of D1 and D2 in PTC compared to changes in the expression of Titf1/Nkx2-1 and Pax-8. Although D1 and D2 activities were decreased in tumor samples (PTC) compared to control C samples (tissues from a nontumorous part of the gland), the differences were not statistically significant. Contrary to that, their mRNA levels were significantly decreased in PTC samples compared to C samples (p = 0.017 and p = 0.012, respectively). Interestingly there was clear discrepancy between enzymatic activity and mRNA level of both deiodinases. There was a statistically significant correlation between D1 and Pax-8 (r = 0.464, p = 0.039), D2 and Pax-8 (r = 0.461, p = 0.041), D2 and Titf1/Nkx2-1 mRNA levels (r = 0.526, p = 0.017). Our results show that changes in D1 and D2 expression in PTC, including the discrepancy between deiodinases activity and mRNA level, might possibly related to impaired Titf1/Nkx2-1 and Pax-8 action.

Thyroid sialyltransferase mRNA level and activity are increased in Graves' disease.

Sialylation of cell components is an important immunomodulating mechanism affecting cell response to hormones and adhesion molecules. To study alterations in sialic acid metabolism in Graves' disease (GD) we measured the following parameters in various human thyroid tissues: lipid-bound sialic acid (LBSA) content, ganglioside profile, total sialyltransferase activity, and the two major sialyltransferase mRNAs for sialyltransferase-1 (ST6Gal I) and for sialyltransferase-4A (ST3Gal I). Fragments of toxic thyroid nodules (TN), nontoxic thyroid nodules (NN) and nontumorous tissue from patients with nodular goiter or thyroid cancer were used as a control (C). The LBSA content and sialyltransferase activity were the highest in the GD group (164 +/- 4.44 versus 120 +/- 2.00 nmoL/g, p = 0.005 and 1625 +/- 283.5 versus 324 +/- 54.2 cpm/mg of protein, p < 0.005 compared to control group C). Ganglioside profile in the GD group was similar to that in control tissues. Sialyltransferase- 1 mRNA and sialyltransferase-4A mRNA levels were significantly higher in the GD group than in the control group (12.52 +/- 6.90 versus 2.54 +/- 1.24 arbitrary units, p < 0.005 and 2,49 +/- 1.16 versus 1.23 +/- 0.46 arbitrary units, p < 0.05, respectively). There was a positive correlation between the increased sialyltransferase-1 mRNA level and the TSH-receptor antibody titer determined by the TRAK test. These results indicate that sialyltransferases expression and activity are increased in GD. Exact mechanism of this upregulation remains unknown, though one of possible explanations is the activation of the thyrotropin (TSH) receptor.

Functionally impaired TR mutants are present in thyroid papillary cancer.

TRs are transcription factors that regulate cell proliferation, differentiation, and apoptosis. They are cellular homologs of the transcriptionally inactive viral oncogene v-erbA. We tested the hypothesis that the functions of TRs could be impaired in cancer tissues as a result of aberrant expression and/or somatic mutations. As a model system, we selected human thyroid papillary cancer, in which the most common abnormalities, RET/papillary thyroid cancer rearrangements (fusion of RET kinase domain to the activating domains of other genes), were found in 40--45% of cases. We found that the mean expression levels of TR beta mRNA and TR alpha mRNA were significantly lower, whereas the protein levels of TR beta 1 and TR alpha 1 were higher in cancer tissues than in healthy thyroid. Sequencing of TR beta 1 and TR alpha 1 cDNAs, cloned from 16 papillary cancers, revealed that mutations affected receptor amino acid sequences in 93.75% and 62.5% of cases, respectively. In contrast, no mutations were found in healthy thyroid controls, and only 11.11% and 22.22% of thyroid adenomas had such TR beta 1 or TR alpha 1 mutations, respectively. The majority of the mutated TRs lost their trans-activation function and exhibited dominant negative activity. These findings suggest a possible role for mutated thyroid hormone receptors in the tumorigenesis of human papillary thyroid carcinoma.

Association of tumor necrosis factor and human leukocyte antigen DRB1 alleles with Graves' ophthalmopathy.

Tumor necrosis factor (TNF)-alpha plays a central role in the development of ophthalmopathy in patients with Graves' disease (GD). The aim of this study was to investigate the association of TNF promoter polymorphisms at positions -1031 (T-1031C), -863 (C-863A), -857 (C-857T), -308 (G-308A), and -238 (G-238A) with Graves' ophthalmopathy (GO). We studied the distribution of TNF and human leukocyte antigen (HLA) DRB1 alleles in 228 Polish white patients with GD, 106 of whom had ophthalmopathy (NOSPECS class > or = III) and 248 healthy subjects. TNF -308A and HLA-DRB1*03 alleles were significantly increased in patients with GD compared with healthy subjects. Stratification analysis revealed no independent association of -308A with GD when the DRB1*03 status was considered. Subdividing GD according to eye involvement revealed that the distribution of TNF promoter haplotypes differed significantly in patients with or without ophthalmopathy. The haplotype containing the -238A allele was absent in GO. The association of G-238A with GO was independent of DRB1 alleles. These results indicate that TNF G-308A is associated with susceptibility to GD (however, this association is not independent of HLA-DRB1*03) and that TNF G-238A is associated with the development of ophthalmopathy, suggesting that G-238A or a gene in linkage disequilibrium may be disease modifying in GD.

Association of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene polymorphism and non-genetic factors with Graves' ophthalmopathy in European and Japanese populations.

OBJECTIVE: The development and severity of Graves' ophthalmopathy (GO) may result from a complex interplay of genetic and environmental factors. The aim of this study was to investigate the association of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene polymorphism and non-genetic factors (age, sex, cigarette smoking) with GO in two different populations, Polish-Caucasians and Japanese. DESIGN: We investigated the distribution of CTLA-4 A49G polymorphism in 264 Caucasian patients with Graves' disease (GD), of which 95 had clinically evident GO (NOSPECS class >or=3) and 319 Japanese patients with GD, of which 99 had ophthalmopathy. The control groups consisted of healthy Polish adults (n=194), Polish centenarians (n=51) and Japanese adults (n=112). RESULTS: Allele G and G/G genotype were significantly increased in Caucasian patients with GD (48% and 25% respectively) and in Japanese patients with GD (69% and 47% respectively) compared with control groups. There were no significant differences in the G allele and G/G genotype frequencies in GO patients compared with GD patients without ophthalmopathy. Multiple logistic regression analysis demonstrated that cigarette smoking (P=0.03, odds ratio (OR)=1.7) and age of onset of GD over 42 Years (P=0.08; OR=1.6) were contributing factors associated with susceptibility to GO in Polish patients. In Japanese patients, a younger age of onset of GD had an effect on the development of GO (P=0.02, OR=1.8). CONCLUSIONS: (i) Allele G and G/G genotype confer genetic susceptibility to GD; (ii) CTLA-4 A49G polymorphism is not associated with the development of GO; (iii) different non-genetic factors may contribute to GO in different populations.

Association of G-174C polymorphism of the interleukin-6 gene promoter with Graves' ophthalmopathy.

Interleukin-6 (IL-6) may play an important role in the pathogenesis of Graves' ophthalmopathy (GO). The aim of this study was to analyze the association of IL-6 gene promoter polymorphism, at position - 174 (G --> C, termed as G-174C), which may affect IL-6 production, with the development of GO. The G-174C polymorphism was determined in 279 Polish-Caucasian patients with Graves' disease (GD), of which 108 had clinically evident ophthalmopathy (NOSPECS class III or higher) and 186 healthy Polish adults. In patients with GD, the frequencies of the C allele (45 vs 42%; P = 0.35) and C/C genotype (20 vs 15%; P = 0.13) were not significantly different compared to controls. Subdividing patients with GD for the presence of eye disease revealed that the C allele (44 vs 45%; P = 0.76) and C/C genotype (20 vs 20%; P = 0.92) were equally distributed in patients with or without ophthalmopathy. There was also no association between the G-174C polymorphism and the severity of eye changes. Finally, IL-6 genotypes were not associated with laboratory findings (thyroid volume, serum IL-6 and thyroid autoantibodies levels) in patients with GD at diagnosis. Our results suggest that G-174C polymorphism of the IL-6 gene does not contribute to the development and severity of GO.

Pax-8 expression correlates with type II 5' deiodinase expression in thyroids from patients with Graves' disease.

Transcription factors TTF-1 and Pax-8 control the expression of thyroid-specific genes crucial for thyroid function. It has been postulated that they may play a role in thyrotropin (TSH)-mediated augmentation of gene expression observed in some thyroid diseases including Grave's hyperthyroidism. Recently, we and others described the expression of two genes participating in thyroid hormone metabolism type I and type II deiodinase (D1 and D2, respectively) that are upregulated by TSH, although the mechanisms responsible for this effect are likely to be different. The aim of this study was to investigate whether there is a correlation between TTF-1 and Pax-8 mRNA levels and type I or type II 5' deiodinases expression in Graves' disease. D1 activity and mRNA level, as well as D2 activity and mRNA level, were significantly increased in Graves' disease in comparison to control tissues. D1, but not D2, activity correlated with its mRNA level in Graves' disease and toxic multinodular goitre. The TTF-1 mRNA level was not different between Graves' disease and control thyroids and no correlation between TTF-1 mRNA level and either D1 or D2 mRNA levels were found. The Pax-8 mRNA level was significantly increased in Graves' disease in comparison to control tissues and correlated with D2, but not D1, mRNA levels among all investigated groups of tissues. Our data suggest that transcription factor Pax-8 could be involved in the upregulation of D2 expression in the thyroid of Graves' patients.

T-cell-mediated immunity in thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is considered to be an autoimmune inflammatory disorder of the extraocular muscles and the orbital fat/connective tissue. Recent studies analyzing T cells infiltrating retrobulbar tissues generated important insights into the immunopathogenesis of TAO. The present review focuses on advances in our understanding of mechanisms responsible for the autoimmune inflammation in TAO, especially T cell migration to the inflammatory site, T cell activation by autoantigens and costimulatory signals and their cytokine profile. The elucidation of these processes might lead to the development of novel therapeutic strategies directed against autoreactive T cells.

Vitamin D receptor binding to DNA is altered without the change in its expression in human renal clear cell cancer.

Vitamin D co-regulates cell proliferation, differentiation and apoptosis, the processes that are disturbed in cancer tissues. It acts through the vitamin D nuclear receptor (VDR) that binds to DNA in the regulatory sequences of the target genes. As the kidney is one of the key organs for vitamin D metabolism and action, we analyzed VDR expression and its DNA binding activity in human renal clear cell cancer. 24 tumors, 24 controls that were excised from the opposite pole of the same kidney and 7 controls originating from kidneys without cancer were examined. Independently of tumor grading neither Northern blots nor immunoblotting demonstrated statistically significant differences of the mean VDR mRNA and protein amounts, respectively, in the cancer as compared to both control types. In contrast, the amount of VDR-DNA complexes was lower in 52.2% of the tumors in comparison to their corresponding controls. After normalization against VDR receptor protein amount in 34.8% of the tumors VDR-DNA binding was at least 3-4 times weaker than in the controls. However, the expression of vitamin D-dependent P21 gene on the mRNA level was not decreased in these cancers. It remains to be elucidated if altered VDR function due to its impaired binding to DNA contributes to the process of tumorigenesis, and what potential vitamin D-dependent mechanisms are involved in this process.

[Management of thyroid diseases during pregnancy]. / Postepowanie w chorobach tarczycy u kobiet w ciazy.

The management of thyroid disorders during pregnancy is one of the most frequently disputed problems in modern endocrinology. It is widely known that thyroid dysfunction may result in subfertility, and, if inadequately treated during pregnancy, may cause obstetrical complications and influence fetal development. The 2007 Endocrine Society Practice Guideline endorsed with the participation of the Latino America Thyroid Association, the American Thyroid Association, the Asia and Oceania Thyroid Association and the European Thyroid Association, greatly contributed towards uniformity of the management of thyroid disorders during pregnancy and postpartum. Despite the tremendous progress in knowledge on the mutual influence of pregnancy and thyroid in health and disease, there are still important areas of uncertainty. There have been at least a few important studies published in the last 3 years, which influenced the thyroidal care of the expecting mother. It should also be remembered that guidelines may not always be universally applied in all populations with different ethnical, socio-economical, nutritional (including iodine intake) background or exposed to different iodine prophylaxis models. The Task Force for development of guidelines for thyroid dysfunction management in pregnant women was established in 2008. The expert group has recognized the following tasks: development of the coherent model of the management of thyroid dysfunction in pregnant women, identification of the group of women at risk of thyroid dysfunction, who may require endocrine care in the preconception period, during pregnancy and postpartum - that is in other words, the development of Polish recommendations for targeted thyroid disorder case finding during pregnancy, and the development of Polish trimester-specific reference values of thyroid hormones. Comprehensive Polish guidelines developed by the Task Force are to systematize the management of the thyroid disorders in pregnant women in Poland.

Association of polymorphism in genes encoding kappaB inhibitors (IkappaB) with susceptibility to and phenotype of Graves' disease: a case-control study.

BACKGROUND: Genes related to the nuclear factor-kappaB (NF-kappaB), a key transcription factor involved in regulation of immune responses, are interesting candidates for association studies in autoimmune disorders. The aim of this study was to investigate an association of polymorphisms in two genes encoding NF-kappaB inhibitors: IKBL (encoding inhibitor of kappaB-like) and NFKBIA (encoding kappaB inhibitor alpha), withsusceptibility to and phenotype of Graves' disease (GD). METHODS: A population-based, case-control association study comprising 481 patients with GD and 455 healthy controls was performed. We analyzed 3 single nucleotide polymorphisms (SNPs) in IKBL [promoter region -62T/A substitution (rs2071592), intron 1 C/T substitution (rs2071591) and exon 4 T/C substitution (rs3130062)] and 3 SNPs in NFKBIA [G/A substitution in 3' untranslated region (rs696) and two promoter region polymorphisms -297C/T (rs2233409) and -826C/T (rs2233406)] by the PCR-restriction fragment length polymorphism (RFLP) method. RESULTS: The two SNPs in IKBL (rs2071592 and rs2071591) were in a strong linkage disequilibrium (D' = 0.835) and the AT haplotype was associated with susceptibility to GD (p < 10-4, OR = 1.61 [95%CI:1.21-2.14]). Moreover subgroup analysis revealed a gen-gen interaction between the investigated IKBL haplotype and HLA-DRB1*03 allele (p < 10-4). The investigated NFKBIA SNPs were not associated with susceptibility to GD. However, when correlated with phenotype, the -297T (rs2233409) and -826T (rs2233406) alleles were associated with the development of clinically evident ophthalmophaty (p = 0.004, pc = 0.07, OR = 1.65 [95%CI: 1.18-2.38] and p = 0.002, pc = 0.036, OR = 1.67 [95%CI: 1.20-2.36], respectively). CONCLUSION: Our results suggest that SNPs in genes encoding NF-kappaB inhibitors may contribute to the development and clinical phenotype of GD.