Differential association of HLA with three subtypes of type 1 diabetes: fulminant, slowly progressive and acute-onset

Abstract

We sought to clarify similarities and differences in the contribution of HLA to genetic susceptibility to three subtypes of type 1 diabetes: acute-onset, fulminant and slowly progressive. We genotyped 545 Japanese patients with type 1 diabetes (338 acute-onset, 80 fulminant, 127 slowly progressive) and 396 control participants at HLA-DRB1, -DQB1, -A, -B and -C, and at 101 candidate single nucleotide polymorphisms (SNPs) in an 8.5 Mb region of the extended HLA. DRB1*0405-DQB1*0401, DRB1*0802-DQB1*0302 and DRB1*0901-DQB1*0303 were associated with acute-onset type 1 diabetes, with the DRB1*0405-DQB1*0401/DRB1*0802-DQB1*0302 genotype achieving the highest odds ratio of 42.7. DRB1*1501-DQB1*0602 and DRB1*1502-DQB1*0601 were negatively associated with acute-onset type 1 diabetes. A similar tendency was observed for slowly progressive type 1 diabetes. In contrast, only DRB1*0405-DQB1*0401 was associated with fulminant type 1 diabetes, with the DRB1*0405-DQB1*0401/DRB1*0405-DQB1*0401 genotype showing the highest odds ratio of 11.2. DRB1*0802-DQB1*0302, DRB1*0405-DQB1*0401/DRB1*0802-DQB1*0302 and DRB1*1501-DQB1*0602 were not associated with fulminant type 1 diabetes. The association of class I alleles and a panel of SNPs in an extended HLA region with fulminant type 1 diabetes was also different from that seen for the acute-onset and slowly progressive forms. The presence of both one and two susceptible haplotypes conferred susceptibility to slowly progressive type 1 diabetes, whereas the presence of two susceptible haplotypes was required to confer susceptibility to acute-onset and fulminant type 1 diabetes. These data suggest that HLA associations with fulminant type 1 diabetes are qualitatively different from those with other subtypes of type 1 diabetes, whereas the HLA contribution to slowly progressive type 1 diabetes is qualitatively similar to, but quantitatively different from, that in acute-onset type 1 diabetes.