HLA DPA1, DPB1 alleles and haplotypes contribute to the risk associated with type 1 diabetes: analysis of the type 1 diabetes genetics consortium families.
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.
Varney
Michael D
MD
Department of Surgery, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA. MVarney@arcbs.redcross.org.au
Valdes
Ana Maria
AM
Carlson
Joyce A
JA
Noble
Janelle A
JA
Tait
Brian D
BD
Bonella
Persia
P
Lavant
Eva
E
Fear
Anna Lisa
AL
Louey
Anthony
A
Moonsamy
Priscilla
P
Mychaleckyj
Josyf C
JC
Erlich
Henry
H
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
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