Genetics of type 1 diabetes with particular focus on the major histocompatibility complex
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AbstractType 1 diabetes (T1D) is a complex, autoimmune disease with a strong heritable component. The single most important genomic region for this and a large number of other diseases is the major histocompatibility complex (MHC), which contains a high density of immune-response genes. In particular, certain variants of the DR and DQ genes are well-known risk factors in T1D, but studies have shown that additional T1D risk loci must exist within the MHC. Their identity has been elusive, however, mainly owing to unusually strong association between variants (linkage disequilibrium) in this complex, which acts as a severe confounding factor. Controlling for these effects is therefore crucial in genetic studies of the MHC.
This thesis goes to the centre of this problem, using a dataset generated by the Type 1 Diabetes Genetics Consortium (T1DGC), which includes several thousand characterised genetic markers in over 2300 T1D families. The statistical power and genetic coverage of the MHC in this dataset is unparalleled by any previous study. In addition, a smaller dataset including over 400 Norwegian families were genotyped for a number of candidate markers. Employing tailored statistical methods and complementary approaches, the results show that at least three defined, narrow regions of the MHC outside of the DR and DQ gene region contain genetic risk factors for T1D. Both novel and previously suggested risk loci are identified. In particular, the evidence for HLA-B as a T1D susceptibility gene is now practically beyond doubt. In addition, a number of previously suggested candidate markers, including in the tumor necrosis factor (TNF) gene, can by all probability be excluded as T1D risk factors. The evidence for other identified variants, in or close to the HLA-A, -C, G and -DPB1 genes, is still somewhat controversial, and will demand further inquiries. These results nonetheless represent important advances in the understanding of the genetic contribution of the MHC to T1D.
List of papers
|1. Eike, M. C., Becker, T., Humphreys, K., Olsson, M. and Lie, B. A (2008). "Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B." Genes Immun. 2009 Jan;10(1):56-67. The paper is not available in DUO. The published version is available at: https://doi.org/10.1038/gene.2008.74|
|2. Eike, M. C., Humphreys, K., Becker, T., Olsson, M., Lie, B. A. and the Type 1 Diabetes Genetics Consortium. “Three microsatellites from the T1DGC MHC dataset show highly significant association with type 1 diabetes, independently of the HLA-DRB1, -DQA1 and DQB1 genes.” Manuskript, akseptert: Diabetes Obes Metab. The paper is not available in DUO.|
|3. Eike, M. C., M. Olsson, et al. (2008). "Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families." Genes Immun. 2009 Mar;10(2):141-50. The paper is not available in DUO. The published version is available at: https://doi.org/10.1038/gene.2008.88|
|4. Eike, M. C., Nordang, G. B., Karlsen, T. H., Boberg, K. M., Vatn, M. H., on behalf of the IBSEN study group, Dahl-Jørgensen, K., Rønningen, K. S., Joner, G., Flatø, B., Bergquist, A., Thorsby, E., Førre, Ø., Kvien, T. K., Undlien, D. E. and Lie, B. A. (2008). "The FCRL3 -169T>C polymorphism is associated with rheumatoid arthritis and shows suggestive evidence of involvement with juvenile idiopathic arthritis in a Scandinavian panel of autoimmune diseases." Ann Rheum Dis 67(9): 1287-91. The paper is not available in DUO. The published version is available at: https://doi.org/10.1136/ard.2007.077826|