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.
| Original language | English |
|---|---|
| Pages (from-to) | 151-161 |
| Number of pages | 11 |
| Journal | Genes and Immunity |
| Volume | 10 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2009 |
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ASJC Scopus subject areas
- Genetics(clinical)
- Immunology
- Genetics
Cite this
The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency. / Haimila, K.; Einarsdottir, E.; de Kauwe, A.; Koskinen, L. L E; Pan-Hammarström, Q.; Kaartinen, T.; Kurppa, K.; Ziberna, F.; Not, T.; Vatta, S.; Ventura, A.; Korponay-Szabo, I. R.; Ádány, R.; Pocsai, Z.; Széles, G.; Dukes, E.; Kaukinen, K.; Mäki, M.; Koskinen, S.; Partanen, J.; Hammarström, L.; Saavalainen, P.
In: Genes and Immunity, Vol. 10, No. 2, 2009, p. 151-161.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency
AU - Haimila, K.
AU - Einarsdottir, E.
AU - de Kauwe, A.
AU - Koskinen, L. L E
AU - Pan-Hammarström, Q.
AU - Kaartinen, T.
AU - Kurppa, K.
AU - Ziberna, F.
AU - Not, T.
AU - Vatta, S.
AU - Ventura, A.
AU - Korponay-Szabo, I. R.
AU - Ádány, R.
AU - Pocsai, Z.
AU - Széles, G.
AU - Dukes, E.
AU - Kaukinen, K.
AU - Mäki, M.
AU - Koskinen, S.
AU - Partanen, J.
AU - Hammarström, L.
AU - Saavalainen, P.
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=61849126866&partnerID=8YFLogxK
U2 - 10.1038/gene.2008.89
DO - 10.1038/gene.2008.89
M3 - Article
C2 - 19020530
AN - SCOPUS:61849126866
VL - 10
SP - 151
EP - 161
JO - Genes and Immunity
JF - Genes and Immunity
SN - 1466-4879
IS - 2
ER -