HLA DPA1, DPB1 Alleles and Haplotypes Contribute to the Risk Associated With Type 1 Diabetes
Analysis of the Type 1 Diabetes Genetics Consortium Families
- Michael D. Varney1,
- Ana Maria Valdes2,
- Joyce A. Carlson3,
- Janelle A. Noble4,
- Brian D. Tait1,
- Persia Bonella4,
- Eva Lavant3,
- Anna Lisa Fear4,
- Anthony Louey1,
- Priscilla Moonsamy5,
- Josyf C. Mychaleckyj6,
- Henry Erlich4,5 and
- for the Type 1 Diabetes Genetics Consortium
- 1Victorian Transplantation & Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Australia;
- 2Department of Twin Research, King's College London, London, UK;
- 3Clinical Chemistry, University Hospital, Malmö, Sweden;
- 4Children's Hospital Oakland Research Institute, Oakland, California;
- 5Roche Molecular Systems, Alameda, California; and
- 6Public Health Sciences, Bioinformatics & Genetics Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
- Corresponding author: Michael D. Varney, .
OBJECTIVE To determine the relative risk associated with DPA1 and DPB1 alleles and haplotypes in type 1 diabetes.
RESEARCH DESIGN AND 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- © 2010 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.