title: Haplotypes in the CTLA4 region are associated with coeliac disease in the Irish population.
abstract: Chromosomal region 2q33 encodes the immune regulatory genes, CTLA4, ICOS and CD28, which are involved in regulation of T-cell activity and has been studied as a candidate gene locus in autoimmune diseases, including coeliac disease (CD). We have investigated whether an association exists between this region and CD in the Irish population using a comprehensive analysis for genetic variation. Using a haplotype-tagging approach, this gene cluster was investigated for disease association in a case-control study comprising 394 CD patients and 421 ethnically matched healthy controls. Several SNPs, including CTLA4_CT60, showed association with disease; however, after correction for multiple-testing, CTLA4-658C/T was the only polymorphism found to show significant association with disease when allele, genotype, or carrier status frequency were analysed (carrier status (Allele C), P = 0.0016). Haplotype analysis revealed a haplotype incorporating the CD28/CTLA4 and two 5' ICOS polymorphisms to be significantly associated with disease (patients 24.1%; controls 31.5%; P = 0.035), as was a shorter haplotype composed of the CTLA4 markers only (30.9 vs 34.9%; P = 0.042). The extended haplotype incorporating CD28/CTLA4 and 5' ICOS is more strongly associated with disease than haplotypes of individual genes. This suggests a causal variant associated with this haplotype may be associated with disease in this population.
authors.affiliation: Department of Clinical Medicine, Trinity College, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland.
authors.forename: K
authors.initials: K
authors.lastname: Brophy
authors.forename: A W
authors.initials: AW
authors.lastname: Ryan
authors.forename: J M
authors.initials: JM
authors.lastname: Thornton
authors.forename: M
authors.initials: M
authors.lastname: Abuzakouk
authors.forename: A P
authors.initials: AP
authors.lastname: Fitzgerald
authors.forename: R M
authors.initials: RM
authors.lastname: McLoughlin
authors.forename: C
authors.initials: C
authors.lastname: O'morain
authors.forename: N P
authors.initials: NP
authors.lastname: Kennedy
authors.forename: F M
authors.initials: FM
authors.lastname: Stevens
authors.forename: C
authors.initials: C
authors.lastname: Feighery
authors.forename: D
authors.initials: D
authors.lastname: Kelleher
authors.forename: R
authors.initials: R
authors.lastname: McManus
mesh_terms: D015703:Antigens, CD / Q000235:genetics*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics; D018106:CD28 Antigens / Q000235:genetics; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D007494:Ireland; D015810:Linkage Disequilibrium
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein