title: The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency.
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.
authors.affiliation: Research and Development, Finnish Red Cross Blood Service, Helsinki, Finland. katri.haimila@bts.redcross.fi
authors.forename: K
authors.initials: K
authors.lastname: Haimila
authors.forename: E
authors.initials: E
authors.lastname: Einarsdottir
authors.forename: A
authors.initials: A
authors.lastname: de Kauwe
authors.forename: L L E
authors.initials: LL
authors.lastname: Koskinen
authors.forename: Q
authors.initials: Q
authors.lastname: Pan-Hammarström
authors.forename: T
authors.initials: T
authors.lastname: Kaartinen
authors.forename: K
authors.initials: K
authors.lastname: Kurppa
authors.forename: F
authors.initials: F
authors.lastname: Ziberna
authors.forename: T
authors.initials: T
authors.lastname: Not
authors.forename: S
authors.initials: S
authors.lastname: Vatta
authors.forename: A
authors.initials: A
authors.lastname: Ventura
authors.forename: I R
authors.initials: IR
authors.lastname: Korponay-Szabo
authors.forename: R
authors.initials: R
authors.lastname: Adány
authors.forename: Z
authors.initials: Z
authors.lastname: Pocsai
authors.forename: G
authors.initials: G
authors.lastname: Széles
authors.forename: E
authors.initials: E
authors.lastname: Dukes
authors.forename: K
authors.initials: K
authors.lastname: Kaukinen
authors.forename: M
authors.initials: M
authors.lastname: Mäki
authors.forename: S
authors.initials: S
authors.lastname: Koskinen
authors.forename: J
authors.initials: J
authors.lastname: Partanen
authors.forename: L
authors.initials: L
authors.lastname: Hammarström
authors.forename: P
authors.initials: P
authors.lastname: Saavalainen
mesh_terms: D015703:Antigens, CD / Q000235:genetics*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics*; D060908:CTLA-4 Antigen; D002446:Celiac Disease / Q000235:genetics*; D017074:Common Variable Immunodeficiency; D005260:Female; D005387:Finland; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D006814:Hungary; D017098:IgA Deficiency / Q000235:genetics*; D060889:Inducible T-Cell Co-Stimulator Protein; D008297:Male; D040641:Quantitative Trait Loci / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein