Combination of HLA-A24, -DQA1*03, and -DR9 contributes to acute-onset and early complete beta-cell destruction in type 1 diabetes: longitudinal study of residual beta-cell function.

To elucidate the genetic factors contributing to heterogeneity of the rate of beta-cell destruction in type 1 diabetes, we investigated the relationship between the time course of complete beta-cell loss and HLA class I and II alleles. HLA allele frequencies were also examined among subgroups classified by the mode of onset. The subjects were 266 type 1 diabetic patients (among whom 196 patients were studied longitudinally) and 136 normal control subjects. Earlier complete loss of beta-cell function was observed in patients who possessed both HLA-A24 and HLA-DQA1*03 and in patients who had HLA-DR9, compared with those without these HLA alleles (P=0.0057 and 0.0093, respectively). Much earlier complete beta-cell loss was observed in the patients who possessed all of HLA-A24, -DQA1*03, and -DR9 compared with the remaining patients (P=0.0011). The combination of HLA-A24, -DQA1*03, and -DR9 showed a higher frequency in acute-onset than slow-onset type 1 diabetes (P=0.0002). In contrast, HLA-DR2 was associated with a slower rate of progression to complete beta-cell loss. These results indicate that the combination of HLA-A24, -DQA1*03, and -DR9 contributes to the acute-onset and early complete beta-cell destruction, whereas HLA-DR2 has a protective effect against complete beta-cell loss in type 1 diabetes.