Human leukocyte antigen class I B and C loci contribute to type 1 diabetes (T1D) susceptibility and age T1D onset

Alleles of human leukocyte antigen (HLA) class 11 genes are well known to affect susceptibility to type I diabetes (T1D), but less is known about the contribution of HLA class I alleles to T1D susceptibility. In this study, molecular genotyping was performed at the HLA-B and HLA-C loci for 283 multiplex Caucasian families, previously typed for HLA-A and the Class II loci. Allele frequencies were compared between affected siblings and affected family-based controls. Linkage disequilibrium coefficients were calculated for HLA-B-HLA-C haplotypes and for class I-class II haplotypes. After adjustment for linkage disequilibrium, the following alleles remain associated with T1D: B*1801, B*3906, B*4403, C*0303, C*0802, and C*1601. B and C allele associations were tested for certain T1D-associated DRB1-DQB1 haplotypes, with the following results: B*3801 is protective on DRBI*0401-DQBI*0302 haplotypes, both C*0701 and C*0702 are predisposing on DRBI*0404-DQBI*0302 haplotypes, and B*3906 is predisposing on DRBI*0801-DQBI*0402 haplotypes. As with previous results for HLA-A, HLA-B and HLA-C are associated with age at T1D onset (mean 11.6 +/- 0.3 years). The protective allele B*4403 was associated with older age at onset (15.1 years; p < 0.04), and the predisposing alleles C*0702 and B*3906 were associated with younger age at onset (9.5 years, p < 0.001; and 7.8 years, p < 0.002, respectively). These data support a role for HLA class I alleles in susceptibility to and age at onset of T1D. (c) American Society for Histocompatibility and Immunogenetics, 2005. Published by Elsevier Inc.