Gene analysis of HLA class II antigens in relation to the development of IDDM in Japanese

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Insulin-dependent diabetes mellitus (IDDM) occurs as a result of destruction of pancreatic beta cells presumably by autoimmune process. It is related to certain HLA antigens, but the HLA types which correlate with IDDM vary among different ethnic groups. In Caucasians, the presence of Asp at HLA DQ B57 protects from IDDM, but many IDDM patients in Japan have Asp at this position. In order to clarify the IDDM susceptibility HLA antigens in Japanese, we analyzed DRB1, DQA1 and DQB1 genes of IDDM patients by polymerase chain reaction and sequence-specific oligonucleotide hybridization. We found that, (1) DR4 and DR9 were positively cor-related while DR2 and DRw11 negatively correlated with IDDM; (2) DR4-Dw15(DRB1*0405), DR9, DQA1*0301, DQB1*0401 alleles were positively correlated with IDDM. As haplotypes, DRB1*0405-DQA1*0301-DQB1*0401(RR=4.4), DRw8-DQA1*0301-DQB1*0302(RR=9.7), and DR9-DQA1*0301-DQB1*0303(RR=2.2) were positively correlated with IDDM. The most susceptible genotype was [DRB1*0405-DQA1*0301-DQB1*0401] / [DRw8-DQA1*0301-DQB1*0302] (RR=18.2); (3) Among 3 families in which a parent and achild had IDDM. DRB1*0405-DQA1*0301-DQB1*0401 was shared in 2 parent-child pairs and DR2-DQA1*0103-DQB1*0601 was shared in one pair. Among 4 IDDM sib pairs, 3 shared two haplotypes, two sharing DRB1*0405-DQA1*0301-DQB1*0401 (homozygotic), and one sharing [DRB1*0403-DQA1*0301-DQB1*0302] / [DRB1*0405-DQA1*0301-DQB1*0401]. One IDDM sib pair shared only one haplotype, DRB1*0405-DQA1*0301-DQB1*0302; (4) Comparison of clinical features and HLA subtypes revealed that DR9, DQA1*0301 and DQB1*0303 were more frequent in CPR-negative patients, and DRB1*0405, DRw8, and DQA1*0401 were more frequent in CPR-positive patients. Patients with thyorid autoantibodies had DR9, DQB1*0303 more often and DRB1*0405, DRw13 and DQA1*0102 less frequently. These data indicate that DRB1, DQA1 and DQB1 genes confer IDDM susceptibility in Japanese and modify clinical features.