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Combination of HLA-A24, -DQA1*03, and -DR9 Contributes to Acute-Onset and Early Complete ß-Cell Destruction in Type 1 Diabetes

Longitudinal Study of Residual ß-Cell Function

¹ Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan
² Okinaka Memorial Institute for Medical Research, Tokyo, Japan
³ Department of Molecular Life Science, Division of Molecular Medical Science and Molecular Medicine, Tokai University Graduate School of Medicine, Kanagawa, Japan

Address correspondence and reprint requests to Koji Nakanishi, MD, PhD, Department of Endocrinology and Metabolism, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan. E-mail: koji01{at}toranomon.gr.jp

Abbreviations: ADA, American Diabetes Association; CPR, C-peptide response; LADA, latent autoimmune diabetes of adults; RFLP, restriction fragment–length polymorphism

To elucidate the genetic factors contributing to heterogeneity of the rate of ß-cell destruction in type 1 diabetes, we investigated the relationship between the time course of complete ß-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 ß-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 ß-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 ß-cell loss. These results indicate that the combination of HLA-A24, -DQA1*03, and -DR9 contributes to the acute-onset and early complete ß-cell destruction, whereas HLA-DR2 has a protective effect against complete ß-cell loss in type 1 diabetes.

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