Haplotypes in the CTLA4 region are associated with coeliac disease in the Irish population.
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.
Brophy
K
K
Department of Clinical Medicine, Trinity College, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland.
Ryan
A W
AW
Thornton
J M
JM
Abuzakouk
M
M
Fitzgerald
A P
AP
McLoughlin
R M
RM
O'morain
C
C
Kennedy
N P
NP
Stevens
F M
FM
Feighery
C
C
Kelleher
D
D
McManus
R
R
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
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