title: HLA DPA1, DPB1 alleles and haplotypes contribute to the risk associated with type 1 diabetes: analysis of the type 1 diabetes genetics consortium families.
abstract: OBJECTIVE
  To determine the relative risk associated with DPA1 and DPB1 alleles and haplotypes in type 1 diabetes.
  
  
  METHODS
  The frequency of DPA1 and DPB1 alleles and haplotypes in type 1 diabetic patients was compared to the family based control frequency in 1,771 families directly and conditional on HLA (B)-DRB1-DQA1-DQB1 linkage disequilibrium. A relative predispositional analysis (RPA) was performed in the presence or absence of the primary HLA DR-DQ associations and the contribution of DP haplotype to individual DR-DQ haplotype risks examined.
  
  
  RESULTS
  Eight DPA1 and thirty-eight DPB1 alleles forming seventy-four DPA1-DPB1 haplotypes were observed; nineteen DPB1 alleles were associated with multiple DPA1 alleles. Following both analyses, type 1 diabetes susceptibility was significantly associated with DPB1*0301 (DPA1*0103-DPB1*0301) and protection with DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 but not DPA1*0201-DPB1*0101. In addition, DPB1*0202 (DPA1*0103-DPB1*0202) and DPB1*0201 (DPA1*0103-DPB1*0201) were significantly associated with susceptibility in the presence of the high risk and protective DR-DQ haplotypes. Three associations (DPB1*0301, *0402, and *0202) remained statistically significant when only the extended HLA-A1-B8-DR3 haplotype was considered, suggesting that DPB1 alone may delineate the risk associated with this otherwise conserved haplotype.
  
  
  CONCLUSIONS
  HLA DP allelic and haplotypic diversity contributes significantly to the risk for type 1 diabetes; DPB1*0301 (DPA1*0103-DPB1*0301) is associated with susceptibility and DPB1*0402 (DPA1*0103-DPB1*0402) and DPA1*0103-DPB1*0101 with protection. Additional evidence is presented for the susceptibility association of DPB1*0202 (DPA1*0103-DPB1*0202) and for a contributory role of individual amino acids and DPA1 or a gene in linkage disequilibrium in DR3-DPB1*0101 positive haplotypes.
authors.affiliation: Department of Surgery, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA. MVarney@arcbs.redcross.org.au
authors.forename: Michael D
authors.initials: MD
authors.lastname: Varney
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Valdes
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Carlson
authors.forename: Janelle A
authors.initials: JA
authors.lastname: Noble
authors.forename: Brian D
authors.initials: BD
authors.lastname: Tait
authors.forename: Persia
authors.initials: P
authors.lastname: Bonella
authors.forename: Eva
authors.initials: E
authors.lastname: Lavant
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Fear
authors.forename: Anthony
authors.initials: A
authors.lastname: Louey
authors.forename: Priscilla
authors.initials: P
authors.lastname: Moonsamy
authors.forename: Josyf C
authors.initials: JC
authors.lastname: Mychaleckyj
authors.forename: Henry
authors.initials: H
authors.lastname: Erlich
mesh_terms: D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology; D005190:Family; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D006682:HLA-DP Antigens / Q000235:genetics*; D059867:HLA-DP alpha-Chains; D059868:HLA-DP beta-Chains; D006239:Haplotypes; D006801:Humans; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: D006680:HLA Antigens; D006682:HLA-DP Antigens; D059867:HLA-DP alpha-Chains; D059868:HLA-DP beta-Chains; C071172:HLA-DPA1 antigen; C071170:HLA-DPB1 antigen