HLA and non-HLA genetic factors in Japanese IDDM.

The HLA of 56 unrelated Japanese with insulin-dependent diabetes mellitus (IDDM) was investigated and reconfirmed their role in the pathogenesis by restriction fragment length polymorphism (RFLP). DQw4 showed the highest correlation to IDDM not only within the DQ system but among all the antigens, suggesting that HLA-DQ might play the most important role in the development of IDDM similar as in Caucasians. When the amino acid sequences of DQA1 and DQB1 alleles were analyzed to find susceptibility to IDDM, common features were observed. That is, in any ethnic group, DQA1 alleles of non-Leu at 76th residue combined with DQB1 alleles of non-Asp at 57th residue show association with IDDM, whereas other combinations give rise to negative association. However, two exceptions were observed in case of Japanese IDDM patients with DQw4 and DQw9. Since DQw4 and DQw9 are in strong linkage disequilibrium with DRB1 containing non-Asp-57th, mixed isotype molecules of DQA1 and DRB1 might be responsible to determine IDDM susceptibility. Furthermore, several non-HLA genes, the polymorphism in the genes encoding the alpha (A), beta (B) and gamma (G) chains of the T-cell receptor (TCRA, TCRB and TCRG), insulin gene (INS) and three closely linked polymorphic genes on chromosome 11q23; Thy-1 (THY1), T3-D (CD3D) and c-ets proto oncogene (ETS1) were analyzed. Only the EST1 gene showed a significant association with IDDM by AvaII-polymorphic fragment (P less than 0.03). These results were discordant with some of the strongly associated genes observed in Caucasians. The discrepancy of the HLA and non-HLA results between both ethnic groups is discussed.