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.

Signatures of strong population differentiation shape extended haplotypes across the human CD28 , CTLA4 , and ICOS costimulatory genes

“…17), and one may question whether a global haplotype protective effect is conferred by 15-2-4 and related extended haplotypes, rather than by single polymorphisms such as CT60. For instance, a recent investigation of susceptibility to celiac disease concluded that an extended haplotype stretching over CD28, CTLA4, and ICOSp was significantly overrepresented in controls and presumably more protective than any one SNP (33). Interestingly, this haplotype partially overlaps with the 15-2-4 haplotype defined here.…”

The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency

“…37 This allele is carried in our risk CTLA4-ICOSe1 haplotype groups 2 and 4, although it is also present in some protective haplotypes. In addition, a study from Ireland reported the protective effect of a C-A-A haplotype in CD; 38 this smaller haplotype occurs frequently in our risk CTLA4-ICOSe1 haplotype group 2 but also exists in the protective haplotype groups 1 and 3. Hence, our results perhaps explain the apparently contradictory results in earlier studies (Table 5c).…”

Impact of Diabetes Susceptibility Loci on Progression From Pre-Diabetes to Diabetes in At-Risk Individuals of the Diabetes Prevention Trial–Type 1 (DPT-1)

“…1B). Similarly, a recent study of the costimulatory locus in patients with celiac disease showed that extended haplotypes in the region demonstrated stronger association with disease susceptibility than individual SNPs (39).…”