Association studies of CTLA-4, CD28, and ICOS gene polymorphisms with type1 diabetes in the Japanese population

Co-stimulatory molecules of CD28, cytotoxic T lymphocyte-associated antigen -4 (CTLA-4), and the newly identified inducible co-stimulator (ICOS) are ex pressed on cell surfaces and provide regulatory signals for T-cell activati on. Their genes are candidate susceptibility genes for type I diabetes beca use they co-localize to Chromosome 2q33 with the IDDM12 locus. After determ ining the genomic structure and screening for polymorphisms of the ICOS gen e, we performed association studies between newly identified polymorphisms of the ICOS gene, together with known polymorphisms of CD28 and CTLA-4 gene s, and type 1 diabetes. The 49A/G dimorphism in exon 1 and the (AT)(n) in t he 3 ' untranslated region of the CTLA-4 gene were significantly associated with type 1 diabetes. Evaluation of the CTLA-4 49A-3 ' (AT)(n) 86-bp haplo type frequency in patients and controls confirmed the results from the anal ysis of each polymorphic site. Dimorphism in intron 3 of the CD28 gene was associated with type 1 diabetes only in the early-onset group. In contrast, there was no association with the microsatellite polymorphisms in the ICOS gene or dimorphisms in the promotor region of CTLA-4. Of the three genes e ncoding co-stimulatory molecules, the CTLA-4 gene appears to confer risks f or the development of type 1 diabetes.