IL-23 Receptor (IL-23R) Gene Protects Against Pediatric Crohn’s Disease

The currently accepted etiopathogenic hypothesis suggests that chronic intestinal inflammation and related systemic manifestations characteristic of inflammatory bowel disease (IBD) are due to an overly aggressive or pathologic immune response to resident luminal bacterial constituents. Predisposing factors are genetic dysregulation of mucosal immune responses and/or barrier function, with onset triggered by environmental stimuli. The increased level of concordance between identical twins, increased rates of IBD among the Ashkenazi Jewish population, and the familial risk of IBD provides strong evidence that genetic factors play an important role in the pathogenesis of IBD.1 Genetic advances have lead to the discovery that variants of CARD15 located at 16q12 and the 5q31 (IBD5) haplotype confer susceptibility to Crohn’s disease (CD). However, the risks associated with these 2 genes account for only a portion of the overall genetic risk. This has led to additional gene findings efforts, the most recent being the recent genome-wide association study that identified the association of the interleukin 23 receptor gene (IL-23R) with small bowel CD. In that study the rare glutamine allele of Arg381Gln (R381Q single nucleotide polymorphism, SNP) conferred protection against CD.2 Distortion of allele transmission was also observed for non-Jewish ulcerative colitis (UC)-affected offspring. This study was conducted in an adult IBD cohort and it remains unknown whether IL-23R is associated with IBD in children. The IL-23R, consisting of an IL-12β1 and an IL-23R chain, is highly expressed on memory T cells.3 IL-23 is a novel cytokine formed via the binding of IL-12p40 to a p19 protein.4 After binding to the IL-23 receptor, IL-23 preferentially activates memory T cells. IL-23 does exhibit some similar biological activities to IL-12, however, IL-12 is more involved in the differentiation of naive T cells into TH1 lymphocytes and subsequent IFNγ production. IL-23, on the other hand, mediates proinflammatory activities in part by the production of IL-17 through activation of TH17 lymphocytes.5 Other research has shown that IL-23 increases IL-6 production that may account for the tissue injury characteristic of IBD.6 It has also been shown that IL-23, not IL-12, is an important promoter of chronic joint inflammation.5 Becker et al7 suggested that there is a predisposition of IL-23-induced chronic inflammation in the terminal ileum, which strengthens the evidence for the recent association between IL-23R in small bowel CD patients.2 The elevation of IL-17 levels in the colonic mucosa of both CD and UC patients, combined with the recent association of IL-23R with UC,2 suggests that IL-23 may also play an important role in UC.8 In this study the association of IL-23R in a pediatric IBD population was tested using the robust method of transmission disequilibrium test (TDT) analysis. We specifically tested R381Q SNP, since this was the most significant result in the genome-wide association study.