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.
Nakanishi
Koji
K
Department of Endocrinology and Metabolism, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan. koji01@toranomon.gr.jp
Inoko
Hidetoshi
H
D000328:Adult; D017668:Age of Onset; D000483:Alleles; D002096:C-Peptide / Q000097:blood / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D005787:Gene Frequency; D015234:HLA-A Antigens / Q000235:genetics*; D059871:HLA-A24 Antigen; D006683:HLA-DQ Antigens / Q000235:genetics; D059848:HLA-DQ alpha-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059810:HLA-DR Serological Subtypes; D006801:Humans; D015994:Incidence; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D007564:Japan / Q000453:epidemiology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012150:Polymorphism, Restriction Fragment Length
D002096:C-Peptide; D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C038988:HLA-DR9 antigen