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Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease. Although the precise mechanisms leading to the destruction of islet beta cells are unknown, diverse studies support a role of the CXCR3-binding chemokines. A combination of a case (n = 447)-control (n = 300) and family (n = 221) analysis was performed to investigate the role of the CXCL9 (rs10336, rs3733236) and CXCL10 (rs3921, rs35795399 and rs8878) polymorphisms and their interaction with HLA high-risk haplotypes DQ2(DQA*0501-DQB*0201)-DQ8(DQA*0301-DQB*0302) in T1D. In addition, the mRNA expression of these genes and of the CXCR3 in peripheral blood mononuclear cells (PBMCs) of T1D patients was studied. In the family analysis, an overtransmission of the allele T and G of the polymorphisms rs35795399 and rs8878 in the whole group (p = 0.0520 and p = 0.0290, respectively) as well as in combination with the HLA-high risk haplotypes (p = 0.0209 and 0.0340, respectively) were observed. In addition, the haplotype rs8878G-rs35795399T was more often transmitted from parents to affected offspring, whereas the haplotype rs8878A-rs35795399C was less often transmitted (p = 0.0130 and p = 0.0201, respectively). Nevertheless these associations did not remain significant after correction for multiple testing, and they could not be corroborated in the case-control analysis. Although we did not find an association of the CXCL9 and CXCL10 polymorphisms with type 1 diabetes in the German population, we cannot discard their role in other populations or other autoimmune diseases.

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: 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.