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Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex

Genes & Immunity volume 10, pages 323–333 (2009)Cite this article

Abstract

The high-risk human leukocyte antigen (HLA)-DRB1, DQA1 and DQB1 alleles cannot explain the entire type 1 diabetes (T1D) association observed within the extended major histocompatibility complex. We have earlier identified an association with D6S2223, located 2.3 Mb telomeric of HLA-A, on the DRB1*03-DQA1*0501-DQB1*0201 haplotype, and this study aimed to fine-map the associated region also on the DRB1*0401-DQA1*03-DQB1*0302 haplotype, characterized by less extensive linkage disequilibrium. To exclude associations secondary to DRB1-DQA1-DQB1 haplotypes, 205 families with at least one parent homozygous for these loci, were genotyped for 137 polymorphisms. We found novel associations on the DRB1*0401-DQA1*03-DQB1*0302 haplotypic background with eight single nucleotide polymorphisms (SNPs) located within or near the PRSS16 gene. In addition, association at the butyrophilin (BTN)-gene cluster, particularly the BTN3A2 gene, was observed by multilocus analyses. We replicated the associations with SNPs in the PRSS16 region and, albeit weaker, to the BTN3A2 region, in an independent material of 725 families obtained from the Type 1 Diabetes Genetics Consortium. It is important to note that these associations were independent of the HLA-DRB1-DQA1-DQB1 genes, as well as of associations observed at HLA-A, -B and -C. Taken together, our results identify PRSS16 and BTN3A2, two genes thought to play important roles in regulating the immune response, as potentially novel susceptibility genes for T1D.

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Acknowledgements

This study was supported by the Juvenile Diabetes Research Foundation International (1-2004-793, 1-2000-514, 1-2000-515), the University of Oslo, the Functional Genomics program (FUGE), the Norwegian Research Council, the Norwegian Diabetes Association, the NovoNordisk Foundation and the Eastern Norway Regional Health Authority. We thank the Norwegian Study Group for Childhood Diabetes, the Danish Study Group of Diabetes in Childhood, the Danish IDDM Epidemiology and Genetics Group, the Swedish Childhood Diabetes Study, the Diabetes Incidence Study in Sweden, the French Network Inserm for IDDM and MS in Atlantic Pyrenees (Dr A Cambon-Thomsen) and the Regional Observatory of health in Aquitaine region (Dr J Doutreix) for the collection of samples used in this study and the bilateral French Norwegian collaborative program AURORA for allowing exchanges and the discussion of analyses. The MassARRAY genotyping service was provided by the national technology platform CIGENE (Centre For Integrative Genetics) supported by the Functional Genomics Program (FUGE) in the Research Council of Norway. This research uses 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), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), the National Institute of Child Health and Human Development (NICHD), and the Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. Resources from the freely available Bioportal (http://www.bioportal.uio.no) were used for some of the statistical analyses. We are grateful to Kristina Gervin and Siri T Flåm for their excellent technical assistance, especially with the SNPlex genotyping, Hege Dahlen Sollid for help with the haplotype analyses and Morten C Eike for assistance with the compilation of the HLA data for the T1DGC families.

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Author notes

  1. M K Viken and A Blomhoff: These authors contributed equally to work.

Authors and Affiliations

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

    M K Viken & E Thorsby

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

    M K Viken, E Thorsby & B A Lie

  3. Faculty Division Ullevål University Hospital, Institute of Medical Genetics, University of Oslo, Oslo, Norway

    A Blomhoff & D E Undlien

  4. Department of Mathematical Statistics, Chalmers University of Technology, Göteborg, Sweden

    M Olsson

  5. Department of Mathematical Statistics, Göteborg University, Göteborg, Sweden

    M Olsson

  6. Department of Medical Genetics, Ullevål University Hospital, Oslo, Norway

    H E Akselsen & D E Undlien

  7. Steno Diabetes Centre, Gentofte, Denmark

    F Pociot & J Nerup

  8. Department of Clinical Neurosciences, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden

    I Kockum

  9. Inserm U 558, University Paul Sabatier, Toulouse, France

    A Cambon-Thomsen

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  1. M K Viken
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Correspondence to B A Lie.

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Viken, M., Blomhoff, A., Olsson, M. et al. Reproducible association with type 1 diabetes in the extended class I region of the major histocompatibility complex. Genes Immun 10, 323–333 (2009). https://doi.org/10.1038/gene.2009.13

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