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HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: Analysis of the Type 1 Diabetes Genetics Consortium families

In English

Författare

  • Henry Erlich
  • Ana Maria Valdes
  • Janelle Noble
  • Joyce Carlson
  • Mike Varney
  • Pat Concannon
  • Josyf C. Mychaleckyj
  • John A. Todd
  • Persia Bonella
  • Anna Lisa Fear
  • Eva Lavant
  • Anthony Louey
  • Priscilla Moonsamy
Visa allt

Summary, in English

OBJECTIVE-The Type 1 Diabetes Genetics Consortium has collected type 1 diabetic families worldwide for genetic analysis. The major genetic determinants of type 1 diabetes are alleles at the HLA-DRB1 and DQB1 loci, with both susceptible and protective DR-DQ haplotypes present in all human populations. The aim of this study is to estimate the risk conferred by specific DR-DQ haplotypes and genotypes. RESEARCH DESIGN AND METHODS:-Six hundred and seven Caucasian families and 38 Asian families were typed at high resolution for the DRB1, DQA1, and DQB1 loci. The association analysis was performed by comparing the frequency of DR-DQ haplotypes among the chromosomes transmitted to an affected child with the frequency of chromosomes not transmitted to any affected child. RESULTS-A number of susceptible, neutral, and protective DR-DQ haplotypes have been identified, and a statistically significant hierarchy of type 1 diabetes risk has been established. The most susceptible haplotypes are the DRB1*0301-DQA1*0501-DQB1*0201 (odds ratio [OR] 3.64) and the DRB1*0405-DQA1*0301-DQB1*0302, DRB1*0401-DQA1*0301-DQB*0302, and DRB1*0402-DQA1*0301-DQB1*0302 haplotypes (ORs 11.37, 8.39, and 3.63), followed by the DRB1*0404-DQA1*0301-DQB1*0302 (OR 1.59) and the DRB1*0801-DQB1*0401-DQB1*0402 (OR 1.25) haplotypes. The most protective haplotypes are DRB1*1501-DQA1*0102-DQB1*0602 (OR 0.03), DRB1*1401-DQA1*0101-DQB1*0503 (OR 0.02), and DRB1*0701-DQA1*0201-DQB1*0303 (OR 0.02). CONCLUSIONS-Specific combinations of alleles at the DRB1, DQA1, and DQB1 loci determine the extent of haplotypic risk. The comparison of closely related DR-DQ haplotype pairs with different type I diabetes risks allowed identification of specific amino acid positions critical in determining disease susceptibility. These data also indicate that the risk associated with specific HLA haplotypes can be influenced by the genotype context and that the trans-complementing heterodimer encoded by DQA1*0501 and DQB1*0302 confers very high risk.

Publiceringsår

2008

Språk

Engelska

Sidor

1084-1092

Publikation/Tidskrift/Serie

Diabetes

Volym

57

Issue

4

Dokumenttyp

Artikel i tidskrift

Förlag

American Diabetes Association Inc.

Ämne

  • Endocrinology and Diabetes

Status

Published

Forskningsgrupp

  • Clinical Chemistry, Malmö

ISBN/ISSN/Övrigt

  • ISSN: 1939-327X