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

• Published in: Diabetologia Vol. 52; no. 12; pp. 2513 - 2521
• Main Authors: Kawabata, Y, Ikegami, H, Awata, T, Imagawa, A, Maruyama, T, Kawasaki, E, Tanaka, S, Shimada, A, Osawa, H, Kobayashi, T, Hanafusa, T, Tokunaga, K, Makino, H
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.12.2009; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Antibodies; Biological and medical sciences; Committees; Diabetes; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - physiopathology; Diabetes Mellitus, Type 1 - prevention & control; Diabetes. Impaired glucose tolerance; Disease Progression; Endocrine pancreas. Apud cells (diseases); Endocrinology; Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Genetic Predisposition to Disease; Genotype; Haplotypes; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class II - genetics; HLA Antigens - genetics; HLA-DQ Antigens - genetics; HLA-DQ beta-Chains; HLA-DR Antigens - genetics; HLA-DRB1 Chains; Hospitals; Human Physiology; Humans; Insulin; Internal Medicine; Introns - genetics; Japan; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Polymorphism; Promoter Regions, Genetic - genetics; Reference Values; Society; Japan; Susceptibility; Type 1 diabetes; Fulminant type 1 diabetes; Genetics; Slowly progressive type 1 diabetes; Single nucleotide polymorphism; HLA; Endocrinopathy; Immunopathology; HLA-System; Autoimmune disease; Sensitivity; Association; Subtype; Polymorphism
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-009-1539-9

Aim/hypothesis 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. Methods 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. Results 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. Conclusions/interpretation 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.