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The aim of our study was to investigate the influence of a 6-month vitamin D supplementation in patients with noninsulin-requiring type 2 diabetes mellitus. We included 86 patients in a placebo-controlled, randomised, double-blind study. During 6 months patients received Vigantol oil once a week corresponding to a daily dose of 1904 IU or placebo oil, followed by 6 months of follow-up. At start and at 3-month intervals 25OHD, PTH, body mass index, HbA1c, insulin, C-peptide, and homeostasis model assessment-index were measured. The primary outcome was a change in fasting blood glucose and insulin levels. After 6 months of therapy, the verum group's 25OHD had increased to a median of 35 ng/ml in comparison to the placebo group (median 20 ng/ml, p10-6). PTH tended to decrease in the verum group (25.5 pg/ml vs. 35.0 pg/ml, p=0.08). After 6 months of therapy, 31 patients (78%) achieved a 25OHD concentration of20 ng/ml. Their HbA1c was significantly lower at baseline (p=0.008) and after therapy (p=0.009) than in patients with 25OHD below 20 ng/ml. C-Peptide, insulin, and HOMA-index did not change significantly in the verum group but fasting insulin was positively correlated with 25OHD concentrations after 6 months of therapy in both groups. There were no significant effects of vitamin D with a daily dose of 1904 IU on metabolic parameters in type 2 diabetes. However, the correlative findings of this study suggest a link of the 25OHD status and metabolic function in type 2 diabetes. Whether vitamin D therapy with higher doses can improve glucose metabolism needs to be investigated in follow-up trials.

Summary Vitamin D (VD) has been implicated in type 1 diabetes (T1D) by genetic and epidemiological studies. Individuals living in regions with low sunlight exposure have an increased T1D risk and VD supplementation reduced the risk in human individuals and mouse models. One possibility of how VD influences the pathogenesis of T1D is its immunomodulatory effect on dendritic cells (DC), which then preferentially activate regulatory T cells (Tregs). In the present pilot study, we collected blood samples from a small cohort of patients with T1D at baseline and months 6 and 12. VD-deficient patients were advised to supplement with 1000 IU/day VD. We found a considerable variation in the VD plasma level at baseline and follow-up. However, with higher VD plasma levels, a lower frequency of interleukin (IL)-4-producing CD8 T cells was observed. We further performed a comprehensive genotyping of 13 VD-related polymorphisms and found an association between VD plasma level and the genotype of the VD binding protein (DBP). The frequency of DC and T cell subsets was variable in patients of all subgroups and in individual patients over time. Nevertheless, we found some significant associations, including the 1,25-dihydroxyvitamin D3 hydroxylase (CYP27B1) genotype with the frequency of DC subtypes. In summary, our preliminary results indicate only a limited influence of the VD plasma level on the immune balance in patients with T1D. Nevertheless, our pilot study provides a basis for a follow-up study with a larger cohort of patients.

Common polymorphisms of the vitamin D receptor gene have been reported to affect the risk of breast, colon, prostate, and differentiated thyroid cancer (DTC), but polymorphisms within the genes of vitamin D metabolizing enzymes have not been studied in DTC. The aim of the present study was to investigate the genes for vitamin D enzymes in patients with DTC and healthy controls (HC) as well as the vitamin D (25-hydroxyvitamin D(3), and 1,25-hydroxyvitamin) status.German patients (n=253) with DTC (papillary thyroid carcinoma [PTC] and follicular thyroid carcinoma [FTC]) and HC (n=302) were genotyped for polymorphisms within the vitamin D metabolizing enzymes such as 25-hydroxylase (CYP2R1[rs12794714, rs10741657]), 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1[rs10877012, rs4646536]), and 25-hydroxyvitamin D 24-hydrolase (CYP24A1[rs927650, rs2248137, rs2296241]). Furthermore, the 25-hydroxyvitamin D(3) [25(OH)D(3)] and 1,25-hydroxyvitamin [1,25(OH)(2)D(3)] plasma levels were measured by a radioimmunoassay.There was no difference in the genotypes; however, the CYP24A1 haplotype analysis showed that rs2248137C/rs2296241A (13.1% vs. 19.1%; corrected p [pc]=0.04) was less frequent in the PTC, whereas the haplotypes rs2248137C/rs2296241G (56.0% vs. 41.9%; pc=0.03), rs927650C/rs2296241G (22.5% vs. 8.4%; pc=1.6×10(-3)), and rs927650C/rs2248137C/rs2296241G (21.1% vs. 7.3%; pc=1.5×10(-3)) were more frequent in the FTC compared with HC. Furthermore, if patients and controls were grouped according to four 25(OH)D(3) categories (severely deficient, deficient, insufficient, and sufficient), then the patients with both DTC subtypes had significantly lower levels of circulating 1,25(OH)(2)D(3), especially in the group with a deficient 25(OH)D(3) status compared with the controls. Although the polymorphisms showed no differences stratified for the four 25(OH)D(3) categories, the activation status by 1,25(OH)(2)D(3) differed significantly depending on the genotypes of the investigated CYP24A1 polymorphisms.A higher risk for DTC is conferred by haplotypes within the CYP24A1 gene, low circulating 25(OH)D(3) levels (deficiency), and a reduced conversion to 1,25(OH)(2)D(3). These results confirm and extend previous observations and also support a role of the vitamin D system in the pathogenesis of DTC. How deficient 25(OH)D(3) levels in combination with certain CYP24A1 haplotypes affect vitamin D activation is the subject of future studies.

Genetic and environmental factors are involved in the pathogenesis of Graves' disease. The human leukocyte antigen (HLA) locus is considered to be one risk factor for Graves' disease but parent of origin effects have not been studied. Therefore, we investigated the transmission of HLA risk haplotypes DQA1*0501, DQA1*0501-DQB1*0201 (DQ2), and DQA1*0501-DQB1*0301 (DQ7) in two Graves' disease family-cohorts from Spain and Germany. Altogether 208 trio-families (109 from Spain and 99 from Germany; n = 624 individuals) with Graves' disease were genotyped for HLA-DQ alleles DQA1*0501 and the haplotypes DQA1*0501-DQB1*0201 (DQ2) and DQA1*0501-DQB1*0301 (DQ7). Since both family groups-German and Spanish-showed the same pattern of HLA transmission and nontransmission, they were analyzed together. HLA DQA1*0501 and DQA1*0501-DQB1*0201 (DQ2) were significantly overtransmitted from the parents to the affected offspring (204 vs. 131, p = 0.0057, pc = 0.0228 and 109 vs. 55, p = 0.0036, pc = 0.0144, respectively). These haplotypes were preferentially transmitted from fathers and DQA1*0501-DQB1*0301 (DQ7) was also more prevalent in fathers (24.0% vs. 17.1%, p = 0.0162, pc = 0.0648). We conclude, that HLA DQA1*0501 and DQA1*0501-DQB1*0201 (DQ2) are strongly associated with Graves' disease in both populations. A parent of origin effect of risk haplotypes can not be excluded at present, warranting further family studies.

BACKGROUND Autoimmune thyroiditis occurs in 10–25% of patients with type 1 diabetes (T1D). Most of these patients are also positive for thyroid peroxidase (TPO) antibodies. Thyroid dysfunction complicates T1D metabolic control and is a component of the autoimmune polyglandular syndrome (APS, type 2 or 3). Previous studies of isolated T1D and of T1D combined with other autoimmune disorders showed genetic susceptibility for alleles in HLA-DQB1 and -DRB1 and also CTLA4 and PTPN22. RESEARCH DESIGN AND METHODS We analyzed the Type 1 Diabetes Genetics Consortium Autoantibody Workshop data by differentiating those T1D probands with and without TPO antibodies or thyroid disease with respect to polymorphisms in HLA, CTLA4, INS, PTPN22, and VDR, taking into account the ethnic origin. Genotype and clinical/immunogenic phenotype data were analyzed by gene counting methods and logistic regression analysis. RESULTS The presence of TPO antibodies (25.2%) and thyroid disease (8.4%) was associated with older age, female sex, and presence of other autoantibodies (GAD65, ATPase, 21-OH) (all P < 0.001). The highest prevalence was in patients of Hispanic ancestry (31%) and the lowest in those of African ancestry (8%). In T1D non-Hispanic whites, HLA-DRB1*0101 is significantly (P < 0.0001) less frequent in TPO-positive than in TPO-negative individuals, whereas HLA-DRB1*0404, -DQB1*0301, and -DPB1*0201 are significantly (P < 0.0001) more frequent. Subjects with a high titer of TPO autoantibodies and with thyroid disease were associated with female sex and older age and negatively associated with DRB1*0401-DQB1*0302 (P < 0.0001). No significant differences were observed for an association of TPO positivity or thyroid disease with single nucleotide polymorphisms in the INS, CTLA4, or VDR loci, with nominal significance (P = 0.01) for PTPN22 R620W variant. CONCLUSIONS Thyroid autoimmunity is highly prevalent in T1D patients of non-Hispanic white, Asian, or Hispanic origin. The strongest disease risk is conferred by female sex and older age. This risk is modulated by HLA-DRB1 and HLA-DPB1 loci. The immunogenetic profile for T1D with thyroid autoimmunity may identify distinct pathways regulating polyglandular autoimmunity and disease.

Background: Endocrine autoimmune disorders share genetic susceptibility loci, causing a disordered T-cell activation and homeostasis (HLA class II genes, CTLA-4). Recent studies showed a genetic variation within the PTPN22 gene to be an additional risk factor. Materials and Methods: Patients with type 1 diabetes (n = 220), Hashimoto’s thyroiditis (n = 94), Addison’s disease (n = 121) and healthy controls (n = 239) were genotyped for the gene polymorphism PTPN22 1858 C/T. Results: Our study confirms a significant association between allelic variation of the PTPN22 1858 C/T polymorphism and type 1 diabetes mellitus (T1D). 1858T was observed more frequently in T1D patients (19.3% vs 11.3%, P = 0.0009; odds ratio for allele T = 1.88, 95% confidence interval [1.3–2.7]). Furthermore, we found a strong association in female patients with T1D (P = 0.0003), whereas there was no significant difference between male patients with type 1 diabetes and male controls. No significant difference was observed between the distribution of PTPN22 C/T in patients with Hashimoto’s thyroiditis or Addison’s disease and healthy controls. Conclusion: The PTPN22 polymorphism 1858 C/T may be involved in the pathogenesis of type 1 diabetes mellitus by a sex-specific mechanism that contributes to susceptibility in females.

Background: Megalin and cubilin bind and internalize the 25(OH)D 3 -DBP complex in the kidney. Once the complex is internalized, 25(OH)D 3 is released and activated to 1,25(OH)2D3 the ligand for the vitamin D receptor (VDR). Supporting the important role of cubilin in this process recent findings showed that cubilin deficiency results in decrease of 25(OH) D 3 and 1,25(OH) 2 D 3 plasma levels. Methods: Two hundred T1D patients and healthy controls (n=200) were genotyped for five polymorphisms (rs3740168, rs3740165, rs1801233, rs1801229 and rs2796835) within the cubilin gene. The polymorphisms were analyzed by RFLP or real time PCR. Statistic analyses were performed by using allele-wise and genotype-wise χ 2 testing by using BiAS software. A p-value < 0.05 was considered as significant. Results: We found that the genotype "AA" of the rs3740165 was more frequent in T1 D patients compared to healthy controls (26.7% vs. 5.1%, p = 4x × 10 -7 ). Nevertheless no association between the rs3740165 polymorphism and the 25(OH)D 3 or 1,25(OH) 2 D 3 plasma levels was found. No association with the other studied polymorphisms was observed. Conclusion: Thus our findings reveal a novel association of the cubilin rs3740165 polymorphism with type 1 diabetes. Nevertheless how exactly this polymorphism could increase the risk to develop type 1 diabetes is subject for further investigations.

Aim: The Major Histocompatibility Complex (MHC) region on chromosome 6p21 (IDDM1) contributes about half of the familial clustering of type 1 diabetes (T1D). Several studies have revealed that highly polymorphic genes within the MHC may associate with the mating choice. Our study should determine whether a specific mating effect is detectable in T1D families as a function of human leucocyte antigen (HLA) DR-DQ, which could contribute to disease susceptibility. Methods: We analysed the parental HLA-DR genotypes in 829 diabetic families. The families derive from the Type 1 Diabetes Genetics Consortium (T1DGC) in addition to those of our own centre and the original UK, US and SCAND diabetic families. Results: A total of 307 of 829 parental couples (37.0%) were matched for at least one known T1D risk haplotype (DR3 or DR4), which is significantly less than the expected 374.9 (45.2%), derived from population genotype frequencies (p

Background Polymorphisms within the insulin gene can influence insulin expression in the pancreas and especially in the thymus, where self-antigens are processed, shaping the T cell repertoire into selftolerance, a process that protects from β-cell autoimmunity. Methods We investigated the role of the -2221Msp(C/T) and -23HphI(A/T) polymorphisms within the insulin gene in patients with a monoglandular autoimmune endocrine disease [patients with isolated type 1 diabetes (T1D, n = 317), Addison's disease (AD, n = 107) or Hashimoto's thyroiditis (HT, n = 61)], those with a polyglandular autoimmune syndrome type II (combination of T1D and/or AD with HT or GD, n = 62) as well as in healthy controls (HC, n = 275). Results T1D patients carried significantly more often the homozygous genotype "CC" -2221Msp(C/T) and "AA" -23HphI(A/T) polymorphisms than the HC (78.5% vs. 66.2%, p = 0.0027 and 75.4% vs. 52.4%, p = 3.7 × 10-8, respectively). The distribution of insulin gene polymorphisms did not show significant differences between patients with AD, HT, or APS-II and HC. Conclusion We demonstrate that the allele "C" of the -2221Msp(C/T) and "A" -23HphI(A/T) insulin gene polymorphisms confer susceptibility to T1D but not to isolated AD, HT or as a part of the APS-II.

Vitamin D has been involved in the modulation of calcium and bone metabolism as well as in the immune system, where it suppresses the proliferation of activated T cells. These effects are exerted via the vitamin D receptor (VDR). Polymorphisms within this gene have been exhaustively studied in diverse autoimmune diseases but with inconsistent results. We previously reported a positive association of polymorphisms within the VDR gene (Apa I, Taq I, Bsm I, and Fok I). In the present article we extended our previous reports to seven additional polymorphisms (rs757343, rs9729, rs2853559, rs1989969, rs3847987, rs2238135, and rs4516035) in a larger set of German simplex type 1 diabetes families. Additionally we correlated serum levels of 25(OH)D(3) and 1,25(OH)(2)D(3) with VDR genotypes and haplotypes. The haplotypes "CG" (Taq I-Apa I), "CGG" (Taq I-Apa I-Tru I), "CGC" (Taq I-Apa I-Fok I), "GCTG" (rs9729-Taq I-Apa I-Tru I), and "CGGC"(Taq I-Apa I, Tru I, Fok I) were less often transmitted, thus negatively associated with type 1 diabetes. Patients who carried the genotype "CC" of the rs3847987 polymorphism had higher median serum levels of 25(OH)D(3). Furthermore, the majority of patients with this genotype possessed normal serum levels of 25(OH)D(3). We conclude that variants of the VDR may confer a genetic protection from type 1 diabetes. Furthermore, normal serum levels of 25(OH)D(3) appear to correlate with a VDR genotype. This supports a role of vitamin D in the immune pathogenesis of type 1 diabetes.

Background Three genes have been confirmed as major joint susceptibility genes for endocrine autoimmune disease:human leukocyte antigen class II, cytotoxic T-lymphocyte antigen 4 and protein tyrosine phosphatase non-receptor type 22. Recent studies showed that a genetic variation within the interferon induced helicase domain 1 (IFIH1) locus (rs1990760 polymorphism) is an additional risk factor in type 1 diabetes and Graves' disease (GD). Methods The aim of the present study was to investigate the role of the rs1990760 polymorphism within the IFIH1 gene in German patients with GD (n = 258), Hashimoto's thyroiditis (HT, n = 106), Addison's disease (AD, n = 195) and healthy controls (HC, n = 227) as well as in 55 GD families (165 individuals, German) and 100 HT families (300 individuals, Italian). Furthermore, the interaction between rs1990760 polymorphism with human leukocyte antigen (HLA) risk haplotype DQ2(DQA*0501-DQB*0201), the risk haplotypes DQ2/DQ8 (DQA*0301-DQB*0302) and the status of thyroglobulin antibody (TgAb), thyroid peroxidase antibody (TPOAb) and TSH receptor antibody (TRAb) in patients and families were analysed. Results No significant differences were found between the allele and genotype frequencies for rs1990760 IFIH1 polymorphism in patients with GD, HT, AD and HC. Also no differences were observed when stratifying the IFIH1 rs1990760 polymorphism for gender, presence or absence of thyroid antibodies (GD:TRAb and HT:TPOAb/TgAb) and HLA risk haplotypes (DQ2:for GD and HT, DQ2/DQ8:for AD). Furthermore the transmission analysis in GD and HT families revealed no differences in alleles transmission for rs1990760 IFIH1 from parents with or without HLA risk haplotype DQ2 to the affected offspring. In contrast, by dividing the HT parents according to the presence or absence of thyroid Ab titers, mothers and fathers both positive for TPOAb/TgAb overtransmitted the allele A of IFIH1 rs1990760 to their HT affected offspring (61.8% vs 38.2%;p = 0.05;corrected p [pc] = 0.1). However, these associations did not remain statistically significant after correction of the p-values. Conclusion In conclusion, our data suggest, no contribution from IFIH1 rs1990760 polymorphism to the pathogenesis of either Graves' disease, Hashimoto's thyroiditis or Addison's disease in our study populations. However, in order to exclude a possible influence of the studied polymorphism in specified subgroups within patients with autoimmune thyroid disease, further investigations in larger populations are needed.