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

Research output: Contribution to journalArticle

Abstract

Type 1 diabetes is a complex disease where numerous genes are involved in the pathogenesis. Genes that account for approximately 50% of the familial clustering of the disease are located within or in the vicinity of the HLA complex on chromosome 6. Some DRB1, DQA1 and DQB1 genes are known to be involved, 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, however, do not carry any of these high-risk HLA class II haplotypes. We have performed genotyping of DRB1, DQA1 and DQB1 alleles in non-DR3-DQ2/non-DR4-DQ8 patients and controls from Sweden and Norway to test if any HLA associations were observed in these patients. Our results clearly demonstrate several statistically significant differences in the frequency of HLA haplotypes between patients and controls. Case-control analysis including the relative predispositional effect test, and transmission disequilibrium test (TDT) analysis in Nonwegian 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 supported 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 that there is a hierarchy of HLA class II haplotypes conferring risk to develop type 1 diabetes.

Details

Authors
  • Dag E. Undlien
  • I. Kockum
  • K. S. Rønningen
  • R. Lowe
  • C. B. Saanjeevi
  • J. Graham
  • B. A. Lie
  • H. E. Akselsen
  • Å Lernmark
  • E. Thorsby
External organisations
  • University of Washington
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes

Keywords

  • Disease susceptibility, Genotype, HLA class II antigens, Insulin-dependent diabetes mellitus, Transmission disequilibrium test (TDT)
Original languageEnglish
Pages (from-to)543-551
JournalTissue Antigens
Volume54
Issue number6
Publication statusPublished - 1999 Dec 1
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes