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The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency

Genes & Immunity volume 10, pages 151–161 (2009)Cite this article

Abstract

IgA deficiency (IgAD) and common variable immunodeficiency (CVID) often co-occur in families, associating with chronic inflammatory diseases such as celiac disease (CD). ICOS (inducible co-stimulator) and CTLA4 (cytotoxic T-lymphocyte-associated protein-4) may be important in both disorders, as ICOS is necessary for Ig class-switching and CTLA4 negatively regulates T-cell activation. Linkage and association of CD with CTLA4-ICOS is well documented, we thus aimed to further pinpoint CD susceptibility by haplotype-tagging analysis. We genotyped 663 CD families from Finland and Hungary, 575 additional CD patients from Finland, Hungary and Italy; 275 Swedish and Finnish IgAD individuals and 87 CVID individuals for 14–18 genetic markers in CTLA4-ICOS. Association was found between CTLA4-ICOS and both IgAD (P=0.0015) and CVID (P=0.0064). We confirmed linkage of CTLA4-ICOS with CD (LOD 2.38, P=0.0005) and found association of CTLA4-ICOS with CD (P=0.0009). Meta-analysis of the IgAD, CVID and CD materials revealed intergenic association (P=0.0005). Disease-associated markers were associated with lower ICOS and higher CTLA4 expression, indicating that the risk haplotypes contain functional variants. In summary, we identified a novel shared risk locus for IgAD, CVID and CD, the first report of association between CTLA4-ICOS and IgAD. Association between CD and CTLA4-ICOS was also confirmed in a large European data set.

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Acknowledgements

We thank Alessandro Bonetti for providing information about the ICOSivs4+1070G/T SNP. Tommy Sund is acknowledged for his help with Figure 1 and Elina Salmela for her help with the forest plot. Hanne Ahola and Anne Heimonen are thanked for their technical assistance. This study and the study groups have been funded by the EU Commission through a Marie Curie Excellence Grant (FP6 contract MEXT-CT-2005-025270), the Academy of Finland, University of Helsinki Research Funds, Biocentrum Helsinki the Competitive Research Funding of the Pirkanmaa Hospital District, EURO-PADnet Health-F2-2008-201549 and the Medical Research Fund of Finnish Red Cross Blood Service.

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  1. K Haimila and E Einarsdottir: These two authors contributed equally to this work.

Authors and Affiliations

  1. Research and Development, Finnish Red Cross Blood Service, Helsinki, Finland

    K Haimila, T Kaartinen, S Koskinen & J Partanen

  2. Department of Medical Genetics and Research Program of Molecular Medicine, University of Helsinki, Helsinki, Finland

    E Einarsdottir, A de Kauwe, L L E Koskinen, E Dukes & P Saavalainen

  3. Department of Clinical Immunology, Karolinska Institute at KUS Huddinge, Stockholm, Sweden

    Q Pan-Hammarström & L Hammarström

  4. Paediatric Research Centre, University of Tampere and Tampere University Hospital, Tampere, Finland

    K Kurppa, K Kaukinen & M Mäki

  5. Department of Reproductive and Development Science, IRCCS ‘Burlo Garofolo’, University of Trieste, Trieste, Italy

    F Ziberna, T Not, S Vatta & A Ventura

  6. Budapest and Department of Pediatrics, Coeliac Disease Center, Heim Pal Children's Hospital, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary

    I R Korponay-Szabo

  7. Department of Preventive Medicine, Faculty of Public Health, University of Debrecen, Debrecen, Hungary

    R Ádány & Z Pocsai

  8. Department of Epidemiology and Biostatistics, Faculty of Public Health, University of Debrecen, Debrecen, Hungary

    G Széles

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  1. K Haimila
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Correspondence to K Haimila.

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Haimila, K., Einarsdottir, E., de Kauwe, A. et al. The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency. Genes Immun 10, 151–161 (2009). https://doi.org/10.1038/gene.2008.89

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