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

K. Haimila, E. Einarsdottir, A. de Kauwe, L. L E Koskinen, Q. Pan-Hammarström, T. Kaartinen, K. Kurppa, F. Ziberna, T. Not, S. Vatta, A. Ventura, I. R. Korponay-Szabo, R. Ádány, Z. Pocsai, G. Széles, E. Dukes, K. Kaukinen, M. Mäki, S. Koskinen, J. PartanenL. Hammarström, P. Saavalainen

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)151-161
Number of pages11
JournalGenes and Immunity
Issue number2
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Genetics(clinical)
  • Immunology
  • Genetics


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