We replicated the association between Graves' disease and PTPN22 'T' reported in British Caucasians. We also found a gene dose-dependent effect of PTPN22 'T' on the age of onset of Graves' disease.

In a Polish population the ESR2 A allele is associated with GD with a strength comparable to polymorphisms of PTPN22 and CTLA4 CT60 loci (OR approximately 1.7). The association with ESR2 is found in both sexes and may be particularly strong among the DRB1*03-negative individuals.

Recently, a functional polymorphism in the NFKB1 gene promoter (À94ins/del ATTG) has been identified and associated with chronic inflammatory diseases. The aim of this study was to analyze the association of NFKB1 polymorphism with susceptibility to and phenotype of Graves' disease (GD). The initial case-control association study, performed in a Polish-Warsaw cohort (388 GD patients and 688 controls), was followed by the two replication studies performed in Polish-Gliwice and JapaneseKurume cohorts (198 GD patients and 194 controls, and 424 GD patients and 222 controls, respectively). The frequency of the À94del ATTG (D) allele was increased in GD compared to controls in Warsaw cohort. This finding was replicated in Gliwice cohort. Combining both Polish-Caucasian cohorts showed that the NFKB1 polymorphism was significantly associated with susceptibility to GD with a codominant mode of inheritance (P ¼ 0.00005; OR ¼ 1.37 (1.18-1.60)). No association with GD was found in Japanese cohort. However, subgroup analysis in Japanese GD patients revealed a correlation between the NFKB1genotype and the development of ophthalmopathy (P ¼ 0.009; OR ¼ 1.49 (1.10-2.01)), and the age of disease onset (P ¼ 0.009; OR ¼ 1.45 (1.09-1.91)). Our results suggest that NFKB1 À94ins/del ATTG polymorphism may be associated with susceptibility to and/or phenotype of GD.

Objectives: The diagnosis and treatment of thyroid diseases in pregnant women remains a challenge. Various medical associations recommend establishing the reference intervals for thyroid hormones by a local laboratory. Considering differences within geophysical, socioeconomic conditions, and iodine prophylaxis in various populations, it is advisable to assess reference intervals for thyroid hormones specific to a region of residence. The objective was to assess trimester-specific reference intervals for TSH, fT₃, and fT₄ for pregnant women in the Polish population. Methods and Results: We conducted a prospective study in 4 centers representing different regions of Poland (Krakow, Warsaw, Poznan, and Bialystok). Our study included consecutive, healthy pregnant women (172 patients), with an age range of 27-47 years. All women had a negative history for thyroid diseases, normal thyroid peroxidase antibody levels, and proper iodine prophylaxis. All newborns had TSH levels in the appropriate reference range. Serum TSH, fT₃, fT₄, and thyroid-peroxidase antibodies were measured in each trimester. The reference intervals were calculated using the percentile method, as recommended by the International Federation of Clinical Chemistry. The reference values calculated were 0.009-3.177, 0.05-3.442, and 0.11-3.53 mIU/L for TSH; 3.63-6.55, 3.29-5.45, and 3.1-5.37 pmol/L for fT₃; and 11.99-21.89, 10.46-16.67, and 8.96-17.23 pmol/L for fT₄ in consecutive trimesters of pregnancy. Reference intervals for pregnant women when compared to the general population showed a lower concentration of TSH in every trimester of pregnancy and lower fT₄ in the 2nd and 3rd trimesters. Conclusions: Using appropriate trimester-specific reference intervals may improve care of pregnant women by preventing misdiagnosis and inadequate treatment.

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.

Thyroid-associated orbitopathy is a set of ophthalmic symptoms resulting from an autoimmune process in which the swelling of extraocular tissues leads to exophthalmos either caused by hypersecretion and accumulation of glycosaminoglycans in the orbit fibroblasts or being the result of inflammatory processes in the oculomotor. These changes cause eyeball motility disturbances, keratopathy, and the pressure on the optical nerve. Thyroid-associated orbitopathy accompanies Graves' disease in most cases, whereas the Hashimoto's disease in only 5%. In the present case, other reasons for the exophthalmos such as tumors of the orbit and sinuses, intracranial tumors, aneurysms and vascular fistulas and orbit tissue inflammation of different etiology were excluded. Additional examinations showed that thyrotropin level was 26 µIU/ml (normal range 0.27-4.0), antithyroglobulin antibody level was 1763 IU/ml (normal range 0-115), antithyrotropin antibody level was 4.93 IU/l (normal range 0-1), and anti-thyroid peroxidase antibody level was 1609 IU/ml (normal range 0-35). An ultrasound examination showed a thyroid gland of 9.8 ml volume. A cytological presentation obtained by thin-needle aspiration biopsy demonstrated inflammatory infiltration of lymphocytes, indicating an autoimmune process. The iodine uptake after 24 hours was 9%. The active form of orbitopathy was diagnosed in the patient with hypothyreosis in the course of Hashimoto's disease. Moreover, the coexistence of another autoimmune disease, pernicious anemia was diagnosed. The administration of the methylprednisolone pulse therapy and levothyroxine caused remission of ophthalmic symptoms, and euthyreosis was obtained. Our report presents a rare coexistence of thyroid orbitopathy and Hashimoto's disease.

Type 1 5'-deiodinase is one of two isoenzymes that participate in conversion of prohormone thyroxine into triiodothyronine (T3). A decrease in type 1 5'-deiodinase expression was observed in renal clear cell carcinoma, thyroid cancer, and lung cancer. The aim of this study was to evaluate type 1 5'-deiodinase activity and mRNA level in breast cancer tissue and non-cancerous surrounding breast tissue. Material was collected from 36 patients undergoing radical mastectomy or local tumor resection. In all non-cancerous breast tissues, type 1 50-deiodinase activity was found to be at a very low or immeasurable level, and type 1 5'-deiodinase mRNA was detected only in 2 out of the 36 samples. By contrast, 20 out of the 36 breast cancer tissues, mainly grades G1 and G2, expressed abundant type 1 5'-deiodinase activity and/or a high mRNA level. Our data demonstrated the presence of type 1 5'-deiodinase in well-differentiated breast cancer tissue. High enzymatic activity of type 1 50-deiodinase can potentially lead to an increase in the production of T3, which may affect target gene transcription, including genes responsible for energy expenditure, growth, differentiation, and proliferation.

The aim of this work was to evaluate whether the FokI and BsmI polymorphisms of the VDR gene are associated with anthropometric and biochemical features of cardiovascular disease (CVD) in a Caucasian population aged over 65, participants of the Polish PolSenior study. We performed the study on randomly selected subjects: 427 women and 454 men aged over 65. Measurements of anthropometric parameters were carried out and biochemical parameters were estimated using commercial kits. VDR polymorphisms (rs10735810, rs1544410) were genotyped by PCR and FRLP. The prevalence of BsmI genotypes was 50% Bb, 23% bb, 27% BB in women and 48% Bb, 20% bb, 32% BB in men. The prevalence of FokI was 48% Ff, 22% ff, 30% FF in women and 50% Ff, 18% ff, 32% FF in men. The women bearing the rare allele b differ in homeostatic model assessment (HOMA) (p < 0.049) from women bearing common allele B, and the men differ in insulin level (p < 0.047) and HOMA (p < 0.017). There were no significant differences in anthropometric or biochemical parameters between genotypes in FokI in female and male groups. The common allele B is connected with biochemical risk factors of CVD in older Caucasian men and women.