Journal
GENES AND IMMUNITY
Volume 10, Issue 2, Pages 151-161Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gene.2008.89
Keywords
IgAD; genetic linkage; association; celia disease
Categories
Funding
- EU Commission [MEXT-CT-2005-025270]
- Academy of Finland
- University of Helsinki Research Funds
- Biocentrum Helsinki the Competitive Research Funding of the Pirkanmaa Hospital District
- EURO-PADnet Health [F22008-201549]
- Medical Research Fund of Finnish Red Cross Blood Service
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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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