Association of the CTLA-4 gene 49 A/G polymorphism with type 1 diabetes and autoimmune thyroid disease in Japanese children

OBJECTIVE - To clarify the role of the T-lymphocyte-associated-4 (CTLA-4) polymorphism in the susceptibility to child-onset type I diabetes with regard to its clinical characteristics and complications with autoimmune thyroid disease (AITD) in the Japanese population. RESEARCH DESIGN AND METHODS - The CTLA-4 49 A/G polymorphism was detected by the PCR-restriction fragment-length polymorphism (RFLP) method in 97 type I diabetic subjects and 20 patients with Graves' disease, a cohort which included 4 patients who also had type I diabetes. RESULTS - The genotypes and allele frequencies of this polymorphism did not differ between the type I diabetic subjects and the control subjects. The G allele frequency was 63.9% in the type I diabetic subjects. The G allele frequency in the subgroup of patients with a high titer of autoantibodies to the GAD antibody (Ab) was 72.9% (P = 0.0499 vs. control subjects); in the subgroup of patients without HLA DRB1 *0405, it was 72.6% (P = 0.0271 vs. control subjects); and in the subgroup of patients with a residual beta-cell function, it was 78.6% (P = 0.0391. vs. control subjects). The G allele frequency in the patients with Graves' disease was also significantly higher at 78.1% (P = 0.0405 vs. control subjects). Furthermore, the frequency in our diabetic subjects complicated with Graves' disease was even higher (87.5%). CONCLUSIONS - We have demonstrated that a distinct association exists between the G allele of CTLA-4 and high values of GAD Ab, residual beta-cell function, and the absence of HLA-DRB1*0405.