Genome-wide analysis of extended pedigrees confirms IL2–IL21 linkage and shows additional regions of interest potentially influencing coeliac disease risk

Authors

  • E. Einarsdottir,

    1. Research Program Unit, Molecular Medicine, University of Helsinki, Helsinki, Finland
    2. Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
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  • L. L. E. Koskinen,

    1. Research Program Unit, Molecular Medicine, University of Helsinki, Helsinki, Finland
    2. Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
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  • A. L. de Kauwe,

    1. Research Program Unit, Molecular Medicine, University of Helsinki, Helsinki, Finland
    2. Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
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  • E. Dukes,

    1. Research Program Unit, Molecular Medicine, University of Helsinki, Helsinki, Finland
    2. Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
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  • K. Mustalahti,

    1. Paediatric Research Centre, School of Medicine, University of Tampere, Tampere, Finland
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  • M. Balogh,

    1. Markusovsky Teaching Hospital, Szombathely, Hungary
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  • I. R. Korponay-Szabo,

    1. Heim Pal Children's Hospital, Budapest, Hungary
    2. Research Centre for Molecular Medicine, University of Debrecen, Debrecen, Hungary
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  • K. Kaukinen,

    1. Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland
    2. School of Medicine, University of Tampere, Tampere, Finland
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  • K. Kurppa,

    1. Paediatric Research Centre, School of Medicine, University of Tampere, Tampere, Finland
    2. Department of Paediatrics, Tampere University Hospital, University of Tampere, Tampere, Finland
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  • R. Ádány,

    1. Faculty of Public Health, Department of Preventive Medicine, University of Debrecen, Debrecen, Hungary
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  • Z. Pocsai,

    1. Faculty of Public Health, Department of Preventive Medicine, University of Debrecen, Debrecen, Hungary
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  • G. Széles,

    1. Faculty of Public Health, Department of Epidemiology and Biostatistics, University of Debrecen, Debrecen, Hungary
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  • M. Mäki,

    1. Paediatric Research Centre, School of Medicine, University of Tampere, Tampere, Finland
    2. Department of Paediatrics, Tampere University Hospital, University of Tampere, Tampere, Finland
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  • J. Kere,

    1. Research Program Unit, Molecular Medicine, University of Helsinki, Helsinki, Finland
    2. Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
    3. Karolinska Institutet, Department of Biosciences and Nutrition, and Clinical Research Centre, Huddinge, Sweden
    4. Folkhälsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland
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  • P. Saavalainen

    Corresponding author
    1. Research Program Unit, Molecular Medicine, University of Helsinki, Helsinki, Finland
    2. Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
      P. Saavalainen, PhD
      Department of Medical Genetics
      Haartman Institute
      Biomedicum Helsinki 1
      PO Box 63
      FIN-00014 University of Helsinki
      Helsinki
      Finland
      Tel: +358-9-19125086
      Fax: +358-9-19125624
      e-mail: paivi.saavalainen@helsinki.fi
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P. Saavalainen, PhD
Department of Medical Genetics
Haartman Institute
Biomedicum Helsinki 1
PO Box 63
FIN-00014 University of Helsinki
Helsinki
Finland
Tel: +358-9-19125086
Fax: +358-9-19125624
e-mail: paivi.saavalainen@helsinki.fi

Abstract

Coeliac disease is a chronic inflammatory condition of the small intestine, triggered by dietary exposure to gluten in genetically susceptible individuals. Risk alleles at HLA-DQA1 and HLA-DQB1 are necessary for disease development, but are alone not sufficient for disease onset. We aimed to identify novel loci underlying susceptibility to coeliac disease through the use of extended Finnish and Hungarian families with multiple affected individuals. An initial whole-genome linkage approach yielded several loci that were followed up further using the Immunochip custom array. Loci with a parametric logarithm of odds (LOD) score of >1.3 were identified at 4q, 6p [human leukocyte antigen (HLA) region], 6q, 7p, 17p, 17q and at 22p. The 4q and 6q loci have been identified previously in coeliac disease risk, whereas follow-up analyses indicate that the 17p and 22p loci may be novel risk loci for coeliac disease. These loci harbour previously described risk variants for other autoimmune diseases, but their segregation patterns do not explain the linkage to coeliac disease. We followed up the linkage to the 4q region, containing the previously described interleukin (IL)2 and IL21 genes. The risk variants at 4q in the studied pedigrees are most likely distinct from previously described risk variants, indicating that the observed linkage may be due to rare high-risk variants of still unknown nature. The importance of this locus to coeliac disease risk was further shown by the finding that serum levels of IL21 were elevated in both untreated and treated coeliac patients compared to controls.

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