Heterozygosity for IL23R p.Arg381Gln Confers a Protective Effect
Heterozygosity for IL23R p.Arg381Gln Confers a Protective Effect
Background: A recent study reported that a non-synonymous single nucleotide polymorphism (rs11209026, p.Arg381Gln) located in the IL23R gene is a protective marker for inflammatory bowel disease.
Aim: To analyse the frequency of p.Arg381Gln in three independent European inflammatory bowel disease cohorts and to evaluate how this variant influences disease behaviour.
Methods: We assessed a European cohort of 919 inflammatory bowel disease patients and compared the IL23R p.Arg381Gln genotype frequency with 845 healthy controls. Inflammatory bowel disease patients originated from Germany [Crohn's disease (CD): n = 318; ulcerative colitis (UC): n = 178], Hungary (CD: n = 148; UC: n = 118) and the Netherlands (CD: n = 157). Ethnically matched controls were included. We performed subtyping analysis in respect to CARD15 alterations and clinical characteristics.
Results: The frequency of the glutamine allele of p.Arg381Gln was significantly lower in inflammatory bowel disease patients compared with controls in a pooled analysis of all three cohorts (P < 0.000001) as well as in the individual cohorts (Germany: P = 0.001, Hungary: P = 0.02 and the Netherlands: P = 0.0002). The p.Arg381Gln genotype distribution was similar between CD and UC. We did not observe either statistical interactions between p.Arg381Gln and CARD15 variants or any significant associations between p.Arg381Gln genotype and subphenotypes.
Conclusions: The p.Arg381Gln IL23R variant confers a protective effect against both CD and UC, but does not determine disease phenotype.
Outstanding progress has been made in the recent years to elucidate the complex genetic background for the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC). The association of CARD15 gene variations to CD has supported the current working hypothesis that CD derives from an aberrant immune response towards intestinal bacteria in a genetically susceptible host.
Although CARD15 variants clearly increase the risk of CD among Caucasians (OR: 18 for homozygotes), it accounts for only 10-15% of cases, which indicates that mutated CARD15 is not sufficient for the development of the disease and that other factors must also play a role. In this respect, a very recent study performed a hypothesis-free genome-wide association study in patients with ileal CD and controls. By single-marker allelic tests, three single nucleotide polymorphisms (SNPs) with significant association with ileal CD were identified. Two SNPs were located within the known CD susceptibility gene, CARD15. The third SNP, rs11209026, was located in the coding sequence of the interleukin 23 receptor (IL23R) gene on chromosome 1p31 and replaces arginine to glutamine in codon 381 [p.Arg381Gln (c.1142G>A)]. The investigated CD populations showed a significantly lower frequency of the heterozygous p.Arg381Gln variant compared with the control populations, suggesting that it protects from the development of CD.
The IL23R gene encodes a subunit of the receptor for IL23 and associates with IL12RB1 to form the IL23 receptor. Interleukin 23 is a heterodimeric protein and a member of the IL12 family. IL23 promotes along with TGF-β1 and IL6 the expansion of the development of proinflammatory IL17-secreting cells. Conflicting reports have been published whether Stat signalling directs the development of Th1-IL17-secreting Th cells. Interleukin-17-secreting T cells have shown to be crucially involved in other autoimmune disease such as rheumatoid arthritis and immunity to infection. Based on these findings, the IL23/Th17 could play a pivotal role in the pathogenesis of IBD. This hypothesis is supported from a recent work, where IL23 acted a driver of both innate and T cell-mediated inflammation in two different mice colitis models.
Numerous genetic variants initially believed to be associated with either CD or UC have failed replication in other cohorts. Thus, it is of fundamental importance to elucidate these variants in other IBD cohorts. In addition, our progress in understanding the genetic background in IBD should go along with the attempt to correlate genotyping results with disease behaviour. In this context, we previously showed that genotyping for CARD15 mutation might be used to identify CD patients with a high risk of post-operative relapse.
Furthermore, an increased intestinal permeability dysfunction is suggested to be crucially involved in the pathogenesis of CD, which has been shown to precede the onset of CD and also to predict relapse. This phenomenon is probably determined at the genetic level. A previous work has identified a clear association of an increase in gastrointestinal permeability to the c.3020insC variant within CARD15. However, the presence of this alteration was not sufficient to explain the complete genetic background of the disturbed epithelial barrier and as a consequence, other genetic variants are likely to be involved. We thus tested for statistical interactions between p.Arg381Gln and results from measurement of gastroduodenal and intestinal permeability in German CD patients.
The aim of this study was threefold. First, we analysed the frequency of the p.Arg381Gln allele in three cohorts of CD and UC patients from Germany, Hungary and the Netherlands to confirm or refute a previous association study. Further, we were interested in the effect of the p.Arg381Gln on the clinical course of IBD. Finally, we tested whether p.Arg381Gln is associated with a disturbed gastrointestinal permeability in CD patients.
Summary and Introduction
Summary
Background: A recent study reported that a non-synonymous single nucleotide polymorphism (rs11209026, p.Arg381Gln) located in the IL23R gene is a protective marker for inflammatory bowel disease.
Aim: To analyse the frequency of p.Arg381Gln in three independent European inflammatory bowel disease cohorts and to evaluate how this variant influences disease behaviour.
Methods: We assessed a European cohort of 919 inflammatory bowel disease patients and compared the IL23R p.Arg381Gln genotype frequency with 845 healthy controls. Inflammatory bowel disease patients originated from Germany [Crohn's disease (CD): n = 318; ulcerative colitis (UC): n = 178], Hungary (CD: n = 148; UC: n = 118) and the Netherlands (CD: n = 157). Ethnically matched controls were included. We performed subtyping analysis in respect to CARD15 alterations and clinical characteristics.
Results: The frequency of the glutamine allele of p.Arg381Gln was significantly lower in inflammatory bowel disease patients compared with controls in a pooled analysis of all three cohorts (P < 0.000001) as well as in the individual cohorts (Germany: P = 0.001, Hungary: P = 0.02 and the Netherlands: P = 0.0002). The p.Arg381Gln genotype distribution was similar between CD and UC. We did not observe either statistical interactions between p.Arg381Gln and CARD15 variants or any significant associations between p.Arg381Gln genotype and subphenotypes.
Conclusions: The p.Arg381Gln IL23R variant confers a protective effect against both CD and UC, but does not determine disease phenotype.
Introduction
Outstanding progress has been made in the recent years to elucidate the complex genetic background for the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC). The association of CARD15 gene variations to CD has supported the current working hypothesis that CD derives from an aberrant immune response towards intestinal bacteria in a genetically susceptible host.
Although CARD15 variants clearly increase the risk of CD among Caucasians (OR: 18 for homozygotes), it accounts for only 10-15% of cases, which indicates that mutated CARD15 is not sufficient for the development of the disease and that other factors must also play a role. In this respect, a very recent study performed a hypothesis-free genome-wide association study in patients with ileal CD and controls. By single-marker allelic tests, three single nucleotide polymorphisms (SNPs) with significant association with ileal CD were identified. Two SNPs were located within the known CD susceptibility gene, CARD15. The third SNP, rs11209026, was located in the coding sequence of the interleukin 23 receptor (IL23R) gene on chromosome 1p31 and replaces arginine to glutamine in codon 381 [p.Arg381Gln (c.1142G>A)]. The investigated CD populations showed a significantly lower frequency of the heterozygous p.Arg381Gln variant compared with the control populations, suggesting that it protects from the development of CD.
The IL23R gene encodes a subunit of the receptor for IL23 and associates with IL12RB1 to form the IL23 receptor. Interleukin 23 is a heterodimeric protein and a member of the IL12 family. IL23 promotes along with TGF-β1 and IL6 the expansion of the development of proinflammatory IL17-secreting cells. Conflicting reports have been published whether Stat signalling directs the development of Th1-IL17-secreting Th cells. Interleukin-17-secreting T cells have shown to be crucially involved in other autoimmune disease such as rheumatoid arthritis and immunity to infection. Based on these findings, the IL23/Th17 could play a pivotal role in the pathogenesis of IBD. This hypothesis is supported from a recent work, where IL23 acted a driver of both innate and T cell-mediated inflammation in two different mice colitis models.
Numerous genetic variants initially believed to be associated with either CD or UC have failed replication in other cohorts. Thus, it is of fundamental importance to elucidate these variants in other IBD cohorts. In addition, our progress in understanding the genetic background in IBD should go along with the attempt to correlate genotyping results with disease behaviour. In this context, we previously showed that genotyping for CARD15 mutation might be used to identify CD patients with a high risk of post-operative relapse.
Furthermore, an increased intestinal permeability dysfunction is suggested to be crucially involved in the pathogenesis of CD, which has been shown to precede the onset of CD and also to predict relapse. This phenomenon is probably determined at the genetic level. A previous work has identified a clear association of an increase in gastrointestinal permeability to the c.3020insC variant within CARD15. However, the presence of this alteration was not sufficient to explain the complete genetic background of the disturbed epithelial barrier and as a consequence, other genetic variants are likely to be involved. We thus tested for statistical interactions between p.Arg381Gln and results from measurement of gastroduodenal and intestinal permeability in German CD patients.
The aim of this study was threefold. First, we analysed the frequency of the p.Arg381Gln allele in three cohorts of CD and UC patients from Germany, Hungary and the Netherlands to confirm or refute a previous association study. Further, we were interested in the effect of the p.Arg381Gln on the clinical course of IBD. Finally, we tested whether p.Arg381Gln is associated with a disturbed gastrointestinal permeability in CD patients.
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