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Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease

Koeleman, Bobby P. C. and Lie, Benedicte Alexandre and Undlien, Dag Erik and Dudbridge, Frank and Thorsby, Erik and De Vries, Rindert R. P. and Cucca, Francesco and Roep, Bart O. and Giphart, M. J. and Todd, John A. (2004) Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease. Genes and Immunity, Vol. 5 (5), p. 381-388. eISSN 1476-5470. Article.

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DOI: 10.1038/sj.gene.6364106

Abstract

Alleles of HLA class II genes DQB1, DQA1, and DRB1 in the MHC region are major determinants of genetic predisposition to type 1 diabetes (T1D). Several alleles of each of these three loci are associated with susceptibility or protection from disease. In addition, relative risks for some DR-DQ genotypes are not simply the sum or product of the single haplotype relative risks. For example, the risk of the DRB1* 03-DQB1* 02/DRB1* 0401-DQB1* 0302 genotype is often found to be higher than for the individual DRB1* 03-DQB1* 02 and DRB1* 0401-DQB1* 0302 homozygous genotypes. It has been hypothesized that this synergy or epistasis occurs through formation of highly susceptible trans-encoded HLA-DQ(α1, β1) heterodimers. Here, we evaluated this hypothesis by estimating the disease associations of the range of DR-DQ genotypes and their inferred dimers in a large collection of nuclear families. We determined whether the risk of haplotypes in DRB1* 0401-DQB1* 0302-positive genotypes relative to the DRB1* 03-DQB1* 02-positive genotypes is different from that of DRB1* 01-DQB1* 0501, which we used as a baseline reference. Several haplotypes showed a different risk compared to DRB1* 01-DQB1* 0501, which correlated with their ability to form certain trans-encoded DQ dimers. This result provides new evidence for the potential importance of trans-encoded HLA DQ molecules in the determination of HLA-associated risk in T1D.

Item Type:Article
ID Code:4200
Status:Published
Refereed:Yes
Uncontrolled Keywords:HLA, type 1 diabetes, genotype risk
Subjects:Area 06 - Scienze mediche > MED/03 Genetica medica
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:Nature Publishing Group
eISSN:1476-5470
Deposited On:16 Jul 2010 12:26

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