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- 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.
- Authors
Varney MD; Valdes AM; Carlson JA; Noble JA; Tait BD; Bonella P; Lavant E; Fear AL; Louey A; Moonsamy P; Mychaleckyj JC; Erlich H; Type 1 Diabetes Genetics Consortium; Varney, Michael D; Valdes, Ana Maria; Carlson, Joyce A; Noble, Janelle A; Tait, Brian D; Bonella, Persia; Lavant, Eva
- Abstract
<bold>Objective: </bold>To determine the relative risk associated with DPA1 and DPB1 alleles and haplotypes in type 1 diabetes.<bold>Research Design and Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Publication
Diabetes, 2010, Vol 59, Issue 8, p2055
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db09-0680