Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus

Abstract

Aims/hypothesis: Fulminant type 1 diabetes, which is characterised by a markedly acute onset of diabetes and an absence of islet-related autoantibodies, accounts for 20% of type 1 diabetes in Japan. We aimed to clarify the contribution of the HLA subtype to fulminant type 1 diabetes in Japanese. Methods: We determined the serological subtypes of HLA-A, -DR and -DQ in 115 patients with fulminant type 1 diabetes, 98 patients with typical type 1A diabetes and 190 normal control subjects. Results: The frequency of HLA-DR4, but not DR9, was significantly higher in fulminant type 1 diabetes, while those of HLA-DR1, DR2, DR5 and DR8 were significantly lower than those in controls. In contrast, DR9 but not DR4 was more frequent and DR2 was extremely rare in typical type 1A diabetes. Haplotype analysis revealed that DR4-DQ4 was significantly more frequent, and both DR2-DQ1 and DR8-DQ1 were less frequent in fulminant diabetes. In type 1A diabetes, DR2-DQ1 was extremely rare while DR9-DQ3 was significantly more frequent. In the combination analysis, the homozygotes of DR4-DQ4 in fulminant type 1 diabetes and DR9-DQ3 in typical type 1A diabetes indicated high odds ratios (13.3 and 13.3, respectively). Conclusions/interpretation: Our results suggest that class II HLA contributes to the development of fulminant type 1 diabetes. Susceptibility and resistance of the HLA subtype to type 1 diabetes are distinct between fulminant and typical autoimmune type 1 diabetes.

Reevaluation of Human Leukocyte Antigen DR-DQ Haplotype and Genotype in Type 1 Diabetes in the Japanese Population

“…A few investigators have demonstrated that the frequencies of DR4, DR9, and DR13 haplotypes are significantly increased in acute-onset type 1 diabetic patients [12, 18]. The average age at onset of diabetes was relatively low in previous studies [6,7,8,9,10, 13 ]which did not find a significant susceptibility to DR13 (8.2–30.1 years)[,] except for one report [11] (34.2 years). The average age at onset of diabetes was relatively high in the report of Murao et al [12] (39.3 years), and, as a result, this group reported a susceptibility to DR13.…”

“…This study demonstrated that the DR13 haplotype confers susceptibility to type 1 diabetes, in addition to DR4, DR8, and DR9 haplotypes which confer susceptibility to type 1 diabetes in Japanese patients [5,6,7,8,9,10,11,12,13]. A few investigators have demonstrated that the frequencies of DR4, DR9, and DR13 haplotypes are significantly increased in acute-onset type 1 diabetic patients [12, 18].…”

“…In the Japanese population, it was demonstrated that some of the DR4/4, DR4/8, DR4/9, DR4/13, DR8/9, DR9/9, and DR9/13 genotypes are significantly increased in frequency in type 1 diabetic patients [6, 7,10,11,12,13, 18]. A synergistic effect of the DR4-DQ8/DR13 genotype was demonstrated in Finnish [23] and Swedish [21, 24] people with and without DR3-DQ2 or DR4-DQ8.…”

“…Previous studies investigating the relationship between HLA class II genes and type 1 diabetes in Japan examined the relationship between HLA class II genes and acute-onset type 1 diabetes [5,6,7,8,9] which might include fulminant type 1 diabetes. In the Japanese population, patients with fulminant type 1 diabetes show differences in HLA-DR or HLA-DQ haplotype involvement as compared with patients with acute-onset type 1 diabetes [10, 11]. On the other hand, there still exists some disagreement in the literature regarding the haplotypes that confer susceptibility to slow-onset type 1 diabetes in the Japanese population [8, 9, 12, 13].…”

Etiopathogenesis of Insulin Autoimmunity

“…The disease may also occur during pregnancy or just after delivery [116, 120]. As a part of the Japanese nationwide survey of FT1DM, it was found that the Class II HLA-DR4-DQ4 (DRB1*04:05-DQB1*04:01) haplotype was significantly more frequent in patients with FT1DM [121]. Interestingly enough, the HLA immunogenetics of pregnancy-associated FT1DM may differ.…”