Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease
| Autor: | Bart O. Roep, Erik Thorsby, Dag E. Undlien, Frank Dudbridge, Bobby P. C. Koeleman, Francesco Cucca, Benedicte A. Lie, John A. Todd, Rindert R. P. De Vries, Marius J. Giphart |
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| Přispěvatelé: | University of Groningen |
| Rok vydání: | 2004 |
| Předmět: |
Male
musculoskeletal diseases Linkage disequilibrium Genotype endocrine system diseases type 1 diabetes Immunology LOCI Human leukocyte antigen SUSCEPTIBILITY Biology HLA-DQB1 ALLELES White People MELLITUS Gene Frequency immune system diseases HLA-DQ Antigens HLA-DQ Genetics Genetic predisposition HLA-DQ beta-Chains Humans Genetic Predisposition to Disease IDDM EXTENDED TRANSMISSION/DISEQUILIBRIUM TEST Allele skin and connective tissue diseases Genetics (clinical) RISK Haplotype genotype risk nutritional and metabolic diseases Epistasis Genetic HLA-DR Antigens PREDISPOSITION RHEUMATOID-ARTHRITIS HLA Diabetes Mellitus Type 1 Haplotypes Case-Control Studies Epistasis Female CLASS-II ALLELES Dimerization HLA-DRB1 Chains |
| Zdroj: | GENES AND IMMUNITY, 5(5), 381-388. Nature Publishing Group |
| ISSN: | 1476-5470 1466-4879 |
| DOI: | 10.1038/sj.gene.6364106 |
| Popis: | 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*02andDRB1*0401-DQB1*0302 homozygous genotypes. It has been hypothesized that this synergy or epistasis occurs through formation of highly susceptible trans-encoded HLA-DQ(alpha1, beta1) 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. |
| Databáze: | OpenAIRE |
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