Association of CTLA-4 polymorphism with positive anti-GAD antibody in Japanese subjects with type 1 diabetes mellitus

CTLA-4, expressed on activated T cells, is thought to be a negative regulator of T cell function. Its gene (2q33) may confer genetic susceptibility to type 1 diabetes mellitus (IDDM12). The present study was undertaken to clarify the role of CTLA-4 gene polymorphism in Japanese subjects with type 1 diabetes and its effect on their clinical features.In 117 Japanese subjects with type 1 diabetes, the CTLA-4 exon 1 polymorphism (49 A/G) was defined by PCR-RFLP analysis. Anti-GAD antibodies (GAD-Ab) and fasting serum C-peptide were also determined. 141 healthy age- and sex-matched subjects served as controls.The frequency of each polymorphism was not different between the type 1 diabetic subjects and the controls; AA 21, AG 42 and GG 54 for the diabetic subjects, and AA 22, AG 47 and GG 72 for the controls. The frequency of the GG genotype was higher in the diabetic subjects with positive GAD-Ab (greater than 8 U/ml) (67%) than in the GAD-Ab negative subjects (39%) (P0.05). The prevalence of positive GAD-Ab declined with the duration of diabetes. In the diabetic subjects with disease duration of less than 5 years (n = 40), the frequency of the GG genotype was also higher in the GAD-Ab positive subjects (71%) (P0.05). In the analysis of all the diabetic subjects, there was a strong association between positive GAD-Ab and beta cell function (P0.0001).There was no evidence that the CTLA-4 exon 1 polymorphism (49 A/G) confers genetic susceptibility to type 1 diabetes mellitus in our case-control study in Japanese subjects. However, the frequency of positive GAD-Ab was higher in the GG subjects. CTLA-4 polymorphism might contribute to the clinical heterogeneity of type 1 diabetes mellitus in Japanese subjects.