Tetsuya Fukushima

Association of Interleukin-18 Gene Promoter Polymorphisms in Type 1 Diabetes and Autoimmune Thyroid Disease

Abstract: Type 1 diabetes is a heterogeneous autoimmune disease and is often associated with other organ‐specific autoimmune diseases, including autoimmune thyroid disease (AITD). IL‐18 is a potent proinflammatory cytokine capable of inducing IFN‐γ production that is associated with the development of type 1 diabetes and AITD. The gene for IL‐18 is located near Idd2 and has been reported to be associated with a susceptibility to type 1 diabetes. To test the putative involvement of IL‐18 gene polymorphism in predisposition to type 1 diabetes and AITD, we conducted a case‐control study in Japanese population. The SNPs at position −607 (C/A) and −137 (G/C) in the promoter region of the IL‐18 gene were analyzed by sequence‐specific PCR in 74 nondiabetic patients with AITD, 47 type 1 diabetic patients with AITD, and 114 normal controls. There was no significant increase in the genotype and allele frequencies not only in nondiabetic patients with AITD compared with normal controls, but also in type 1 diabetic patients with AITD compared with normal controls. The distribution of IL‐18 gene haplotypes was also similar between both patient groups and normal controls. These results suggest that polymorphisms of the IL‐18 gene are not associated with a susceptibility to AITD and type 1 diabetes coexistent with AITD in Japanese population.

Stromal Cell-Derived Factor-1 Chemokine Gene Variant in Patients with Type 1 Diabetes and Autoimmune Thyroid Disease

Abstract: Type 1 diabetes is a heterogenous autoimmune disease and is frequently associated with other organ‐specific autoimmune diseases, including autoimmune thyroid disease (AITD). Type 1 diabetic patients with AITD are known to have clinical and immunological features distinct from patients without AITD. This study investigated whether stromal cell‐derived factor (SDF)‐1 gene polymorphism is associated with susceptibility to type 1 diabetes and AITD. SDF‐1 is a powerful chemokine that upregulates T‐cell migration and activation, and the gene for SDF‐1 is located near type 1 diabetes susceptibility locus IDDM10. The SDF1‐3′A variant (801 G to A in the 3′‐untranslated region) was determined by the PCR‐RFLP technique in 54 type 1 diabetic patients with AITD, 75 type 1 diabetic patients without AITD, 137 nondiabetic patients with AITD, and 106 healthy subjects in a case‐control study. No significant differences on the allele and genotype frequencies of the SDF1 gene polymorphism were found, not only in type 1 diabetic patients with AITD compared with normal controls but also between nondiabetic patients with AITD and healthy control subjects. These results suggest that the SDF1‐3′A variant is not associated with genetic susceptibility to type 1 diabetic patients and AITD.

Epitope Analysis of GAD65 Autoantibodies in Japanese Patients with Autoimmune Diabetes

Abstract: Type 1 diabetes is an organ‐specific autoimmune disease characterized by T cell‐mediated destruction of pancreatic β cells. In Japanese population, the incidence of type 1 diabetes in children is very low compared to European countries. However, there are more patients with type 1 diabetes in adults, including latent autoimmune diabetes in adults (LADA). The circulating autoantibodies to multiple islet autoantigens including GAD, insulin, and IA‐2 are the important immunological features of type 1 diabetes. The prevalences of anti‐islet autoantibodies in patients with Japanese type 1 diabetes are 60‐70% for GAD autoantibodies, 45‐50% for insulin autoantibodies (IAA), and 60‐65% for IA‐2 autoantibodies at disease onset, which are similar to those reported in Caucasian patients. With combinatorial analysis of these autoantibodies, 90% of patients express at least one of these autoantibodies and are classified as type 1A diabetes. Although the majority of patients with type 1 diabetes are young, lean, and ketosis‐prone, there are a number of patients with type 1 diabetes initially diagnosed as having type 2 diabetes at disease onset called LADA. These patients with LADA often progress toward an insulin‐deficient state within several years after diagnosis. High levels of GAD autoantibodies have a high predictive value for future insulin deficiency in LADA. Further, epitope analysis of GAD65 autoantibodies may be helpful to predict future insulin dependency in LADA patients. In conclusion, Japanese patients with type 1 diabetes are clinically heterogeneous and the determination of immunological features are helpful to clarify the characteristics of the Japanese type 1 diabetic syndrome.

Interleukin-10 Gene Promoter Region Polymorphisms in Patients with Type 1 Diabetes and Autoimmune Thyroid Disease

Abstract: Type 1 diabetes is a heterogeneous autoimmune disease and is frequently associated with other organ‐specific autoimmune diseases, including autoimmune thyroid disease (AITD). Type 1 diabetic patients with AITD are known to show distinct clinical and immunological features from patients without AITD. This study investigated whether interleukin‐10 (IL‐10) gene promoter region polymorphisms are associated with susceptibility to type 1 diabetes and AITD. The frequency of −1082G/A, −819C/T, and −592C/A polymorphisms was analyzed in 54 type 1 diabetic patients with AITD, 74 type 1 diabetic patients without AITD, 124 nondiabetic patients with AITD, and 107 healthy subjects in a case‐control study. No significant differences on the allele and genotype frequencies of three polymorphisms were found not only in type 1 diabetic patients with AITD compared with normal controls, but also between nondiabetic patients with AITD and healthy controls. The distribution of IL‐10 gene haplotypes was also similar between both patient groups and normal controls. These results suggest that IL‐10 gene promoter region polymorphisms are not associated with genetic susceptibility to type 1 diabetes and AITD.