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Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B

Genes & Immunity volume 10, pages 56–67 (2009)Cite this article

Abstract

The major histocompatibility complex (MHC) is known to harbour genetic risk factors for type 1 diabetes (T1D) additional to the class II determinants HLA-DRB1, -DQA1 and -DQB1, but strong linkage disequilibrium (LD) has made efforts to establish their location difficult. This study utilizes a dataset generated by the T1D genetics consortium (T1DGC), with genotypes for 2965 markers across the MHC in 2321 T1D families of multiple (mostly Caucasian) ethnicities. Using a comprehensive approach consisting of complementary conditional methods and LD analyses, we identified three regions with T1D association, independent both of the known class II determinants and of each other. A subset of polymorphisms that could explain most of the association in each region included single nucleotide polymorphisms (SNPs) in the vicinity of HLA-G, particular HLA-B and HLA-DPB1 alleles, and SNPs close to the COL11A2 and RING1 genes. Apart from HLA-B and HLA-DPB1, all of these represent novel associations, and subpopulation analyses did not indicate large population-specific differences among Caucasians for our findings. On account of the unusual genetic complexity of the MHC, further fine mapping is demanded, with the possible exception of HLA-B. However, our results mean that these efforts can be focused on narrow, defined regions of the MHC.

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Acknowledgements

This research utilizes resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD) and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. MC Eike and BA Lie were supported by JDRF Grant 1-2004-793, by the Novo Nordisk Foundation and the Norwegian Diabetes Association. K Humphreys acknowledges support from the Swedish Research Council. M Olsson was supported by SSF Grant A3 02:129.

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Authors and Affiliations

  1. Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway

    M C Eike & B A Lie

  2. Faculty Division Rikshospitalet, Institute of Immunology, University of Oslo, Oslo, Norway

    M C Eike

  3. Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany

    T Becker

  4. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    T Becker, K Humphreys & M Olsson

  5. Mathematical Statistics, Chalmers University of Technology, Gothenburg, Sweden

    M Olsson

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  1. M C Eike
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Correspondence to M C Eike.

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Eike, M., Becker, T., Humphreys, K. et al. Conditional analyses on the T1DGC MHC dataset: novel associations with type 1 diabetes around HLA-G and confirmation of HLA-B. Genes Immun 10, 56–67 (2009). https://doi.org/10.1038/gene.2008.74

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