Abstract
BackgroundThe CTLA4 (cytotoxic T-lymphocyte antigen 4) gene is associated with several immunopathologic diseases and because of its important immuno-regulatory role it may be considered also a plausible candidate for a genetic association with inflammatory bowel diseases. Previously published studies found no association of CTLA4 with Crohn's disease itself, but some indicated an association with its subphenotypes. The aim of this study was to assess the association in the Czech population, using a set of markers shown to associate with other diseases.MethodsSix polymorphisms within the CTLA4 region were investigated in 333 patients with Crohn's disease and 482 unrelated healthy controls, all Caucasians of Czech origin. The genotypes of the SNPs were determined using the TaqMan SNP genotyping assays. Haplotypes were reconstructed using an expectation-maximization algorithm, and their association with the condition was assessed using log-linear modeling. Then, potential interactions were tested between the CTLA4 variants and other genetic factors known to confer the disease susceptibility.ResultsNo crude associations with Crohn's disease were found for the tested CTLA4 variants under the log-additive or dominant models. However, when stratified for the genetic risk conferred by the variants in the NOD2 (the p.Leu1007fsX1008, rs5743293) or the IL23R (p.R381Q, rs11209026), a significant negative association emerged for the minor alleles of CTLA4 CT60 (rs3087243), JO31 (rs11571302), JO27-1 (rs11571297) polymorphisms. This negative association with CTLA4 was apparent only in the strata defined by presence minor alleles at the NOD2 rs5743293 (here the CTLA4 CT60 A coffered an OR = 0.43, 95%CI 0.19 - 0.95 for the presence of CT60 A), or IL23R rs11209026 (here the OR for presence of CT60 A was 0.23, 95%CI 0.07 - 0.71). We observed this effect also for the haplotype consisting of minor alleles of the three tightly linked CTLA4 markers. Furthermore, this haplotype was associated with the younger age at diagnosis (OR 1.52, 95%CI 1.09 - 2.11, p = 0.014).ConclusionsA protective effect of a CTLA4 haplotype was unmasked after stratification for the risk variants in the NOD2 and IL23R genes, and may point towards the biological relevance of the molecule in the pathogenesis of the disease.
Highlights
The cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene is associated with several immunopathologic diseases and because of its important immuno-regulatory role it may be considered a plausible candidate for a genetic association with inflammatory bowel diseases
No crude associations with Crohn's disease (CD) were found for the tested single nucleotide polymorphisms (SNPs) under the log-additive or dominant models
The genotype distributions in control subjects conformed to Hardy-Weinberg equilibrium in all SNPs (p > 0.20) except the rs1427676 (p = 0.014 in exact tests) which was excluded from all further analyses
Summary
The CTLA4 (cytotoxic T-lymphocyte antigen 4) gene is associated with several immunopathologic diseases and because of its important immuno-regulatory role it may be considered a plausible candidate for a genetic association with inflammatory bowel diseases. Published studies found no association of CTLA4 with Crohn's disease itself, but some indicated an association with its subphenotypes. The aim of this study was to assess the association in the Czech population, using a set of markers shown to associate with other diseases. The CTLA4 gene may be considered as a plausible candidate for a genetic association with IBD. Published papers about genetic association with CD tested three variants in the CTLA4 gene: g.49A > G (rs231775), g.-318C > T (rs5742909) and the previously mentioned CT60, having found no association [18,19,20,21]. Several works suggested that CTLA4 variants may influence the phenotype of CD [18,19]
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