CTLA4 gene polymorphism contributes to the mode of onset of diabetes with antiglutamic acid decarboxylase antibody in Japanese patients: genetic analysis of diabetic patients with antiglutamic acid decarboxylase antibody

Aim The mode of onset is occasionally similar in Type 1 and Type 2 diabetes mellitus, and some patients with Type 2 diabetes are positive for antiglut amic acid decarboxylase antibody (GAD Ab). We investigated the contribution of Type 1 diabetes susceptibility genes to the progression of the insulin- deficient state and mode of onset of Type 2 diabetes in GAD Ab-positive (GA D-Ab(+)) patients. We examined the variable number of tandem repeats in the promoter region of the insulin gene (INS-VNTR, insulin-dependent diabetes mellitus (IDDM) 2) and cytotoxic T lymphocyte antigen 4 (CTLA4, IDDM12) as representative of Type 1 diabetes susceptibility genes. Methods Patients with Type 2 diabetes who were GAD-Ab(+) (n = 51) were sele cted for this study. In INS-VNTR, the class I allele was classified accordi ng to length (1S, 25-38 repeat units; 1M, 39-41 repeat units; 1L, 42-44 rep eat units) and the exact class I allele length was analysed by specific pol ymerase chain reaction (PCR) amplifications. Analyses of classes II and III were performed by Southern blot. CTLA4 gene polymorphism (exon 1 position 49, G/A) was analysed by PCR-restriction fragment length polymorphism. Results The distribution of INS-VNTR was no different between Type 1 diabet es and Type 2 diabetes with GAD Ab. The allele frequencies of CTLA4 gene po lymorphism G and A in Type 2 diabetes/GAD-Ab(+) were significantly differen t from those of Type 1 diabetes/GAD-Ab(+) (G: 53%, A: 47% vs. G: 84%, A: 16 %; P < 0.0001). Conclusions Our data showed that GAD-Ab(+) Japanese patients presenting wit h Type 2 diabetes have shifted A allele while patients with abrupt onset ha ve shifted G allele of CTLA4 gene polymorphism. Our results suggest that im munological function and polymorphism of the CTLA4 gene may contribute to t he pathogenesis and progression of Type 1 diabetes.