title: HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families.
abstract: 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.
  
  
  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 1 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.
authors.affiliation: Roche Molecular Systems, 1145 Atlantic Ave., Alameda, CA 94501, USA. Henry.Erlich@Roche.com
authors.forename: Henry
authors.initials: H
authors.lastname: Erlich
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Valdes
authors.forename: Janelle
authors.initials: J
authors.lastname: Noble
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Carlson
authors.forename: Mike
authors.initials: M
authors.lastname: Varney
authors.forename: Pat
authors.initials: P
authors.lastname: Concannon
authors.forename: Josyf C
authors.initials: JC
authors.lastname: Mychaleckyj
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.forename: Persia
authors.initials: P
authors.lastname: Bonella
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Fear
authors.forename: Eva
authors.initials: E
authors.lastname: Lavant
authors.forename: Anthony
authors.initials: A
authors.lastname: Louey
authors.forename: Priscilla
authors.initials: P
authors.lastname: Moonsamy
mesh_terms: D017668:Age of Onset; D044466:Asian People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics*; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; C553505:HLA-DRB1*04:01 antigen; C553506:HLA-DRB1*04:02 antigen