HLA associations in type 1 diabetes among patients not carrying high-risk DR3-DQ2 or DR4-DQ8 haplotypes

Type 1 diabetes is a complex disease where numerous genes are involved in t he pathogenesis. Genes that account for approximately 50% of the familial c lustering of the disease are located within or in the vicinity of the HLA c omplex on chromosome 6. Some DRB1, DQA1 and DQB1 genes are known to be invo lved, in addition to as yet unidentified HLA-linked genes. The DR4-DQ8 and DR3-DQ2 haplotypes are known to confer high risk for developing the disease , particularly when occurring together. Approximately 10% of patients, howe ver,do not carry any of these high-risk HLA class II haplotypes. We have pe rformed genotyping of DRB1, DQA1 and DQB1 alleles in non-DR3-DQ2/non-DR4-DQ 8 patients and controls from Sweden and Norway to test if any HLA associati ons were observed in these patients our results clearly demonstrate several statistically significant differences in the frequency of HLA haplotypes b etween patients and controls. Case-control analysis including the relative predispositional effect test, and transmission disequilibrium test (TDT) an alysis in Norwegian type 1 diabetes families revealed that the DQA1*03-DQB1 *0301, DQA1*0401-DQB1*0402, DQA1*0101-DQB1*0501, DQA1*03-DQB1*0303 and DQA1 *0102-DQB1*0604 haplotypes may also confer risk. Our analyses also supporte d independent risks of certain DRB1 alleles. The study clearly demonstrates that HLA associations in type 1 diabetes extends far beyond the well-known associations with the DR4-DQ8 and DR3-DQ2 haplotypes. Our data suggest tha t there is a hierarchy of HLA class II haplotypes conferring risk to develo p type 1 diabetes.