IL23R Arg381Gln is associated with childhood onset inflammatory bowel disease in Scotland

Limbergen, Johan Van; Russell, Richard K.; Nimmo, Elaine R.; Drummond, Hazel E.; Smith, Linda A.; Davies, Gail; Anderson, Niall; Gillett, Peter M.; McGrogan, Paraic; Hassan, Kamal; Weaver, Lawrence T.; Bisset, W M; Mahdi, Gamal; Wilson, David C.; Satsangi, Jack

doi:10.1136/gut.2007.122069

Cited by 80 publications

(56 citation statements)

References 15 publications

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“…Other variants within IL23R are also associated with IBD, independent of the Arg381Gln association. Since the initial report, these findings have subsequently been replicated in Scottish pediatric IBD [121] and Belgian CD [119] cohorts, indicating a clear role for IL23R in IBD susceptibility.…”

Section: Il23r Is Associated With CD and Ucmentioning

confidence: 74%

Inflammatory bowel disease: Genetic and epidemiologic considerations

Cho

2008

WJG

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Genome-wide association studies have firmly established that many genomic loci contribute to inflammatory bowel disease, especially in Crohn's disease. These studies have newly-established the importance of the interleukin 23 and autophagy pathways in disease pathogenesis. Future challenges include: (1) the establishment of precisely causal alleles, (2) definition of altered functional outcomes of associated and causal alleles and (3) integration of genetic findings with environmental factors.

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Section: Il23r Is Associated With CD and Ucmentioning

confidence: 74%

Inflammatory bowel disease: Genetic and epidemiologic considerations

Cho

2008

WJG

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“…Detailed genetic characterization VE Garcia et al diseases including IBD (particularly adult and pediatric Crohn's disease), [16][17][18][19][20][21][22][23][24] AS, 25,26 and GO. 27 It is possible that IL23R variants also underlie susceptibility to celiac disease, 28 Graves' disease without ophthalmopathy 27 and multiple sclerosis, 28,29 although the evidence is not currently strong for celiac disease and Graves' disease without opthalmopathy and is contradictory for multiple sclerosis.…”

Section: Discussionmentioning

confidence: 99%

“…11 These results have been verified in four independent studies [12][13][14][15] and have paralleled association studies in related diseases. One of the IL23R missense SNPs implicated in psoriasis, R381Q, has also been strongly associated with several autoinflammatory phenotypes: several studies have found R381Q-mediated predisposition to adult inflammatory bowel disease (IBD), especially Crohn's disease [16][17][18][19][20][21] and pediatric Crohn's disease in individuals of European descent, [22][23][24] two sizable studies reported association of multiple IL23R SNPs with ankylosing spondylitis (AS) 25,26 and a North American study demonstrated IL23R susceptibility for Graves' ophthalmopathy (GO). 27 IL23R polymorphisms have also been studied in celiac disease with mildly significant results 28 and multiple sclerosis with conflicting results.…”

Section: Introductionmentioning

confidence: 99%

Detailed genetic characterization of the interleukin-23 receptor in psoriasis

García¹,

Chang²,

Brandon³

et al. 2008

Genes Immun

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Using a multi-tiered, case-control association design, scanning 25 215 gene-centric SNPs, we previously identified two psoriasis susceptibility genes: IL12B and IL23R. These results have recently been confirmed. To better characterize the IL23R psoriasis-association, we used a fine mapping strategy to identify 59 additional IL23R-linked SNPs, which were genotyped in our three independent, white North American sample sets (42800 individuals in toto). A sliding window of haplotype association demonstrates colocalization of psoriasis susceptibility effects within the boundaries of IL23R across all sample sets, thereby decreasing the likelihood that neighboring genes, particularly IL12RB2, are driving the association at this region. Additional haplotype work identified two 5-SNP haplotypes with strong protective effects, consistent across our three sample sets (OR common ¼ 0.67; P comb ¼ 4.32E-07). Importantly, heterogeneity of effect was extremely low between sample sets for these haplotypes (P Het ¼ 0.961). Together, these protective haplotypes attain a frequency of 16% in controls, declining to 11% in cases. The characterization of association patterns within IL23R to specific predisposing/protective variants will play an important role in the elucidation of psoriasis etiology and other related phenotypes. Further, this work is essential to lay the foundation for the role of IL23R genetics in response to pharmaceutical therapy and dosage.

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“…Increases in p19 expression were reported in intestinal mucosal biopsies from CrD and UC patients, but not in non-IBD colitis patients (58,59), and a nonsynonymous variant of the IL-23R has been reported as one of the three markers associated with childhood onset of IBD (the other two markers being located in the NOD2/CARD15 gene) (60). In a model of spontaneous colitis, p19-deficient mice were shown to be disease resistant, and IL-23 administration together with transfer of CD4 ϩ CD45RB high T cells into Rag-1-deficient mice significantly accelerated disease onset (19).…”

Section: Discussionmentioning

confidence: 99%

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

Sheibanie

Yen

Khayrullina

et al. 2007

The Journal of Immunology

252

196

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Although Crohn’s disease has been traditionally considered to be Th1-mediated, the newly identified Th17 cells emerged recently as crucial participants. Th1/Th17 differentiation is controlled primarily by the IL-12 family of cytokines secreted by activated dendritic cells (DCs) and macrophages. IL-23 and IL-12/IL-27 have opposite effects, supporting the Th17 and Th1 phenotypes, respectively. We found that PGE2, a major lipid mediator released in inflammatory conditions, shifts the IL-12/IL-23 balance in DCs in favor of IL-23, and propose that high levels of PGE2 exacerbate the inflammatory process in inflammatory bowel disease through the IL-23→IL-17 axis. We assessed the effects of PGE2 on IL-12, IL-27, and IL-23 and found that PGE2 promotes IL-23, inhibits IL-12 and IL-27 expression and release from stimulated DCs, and subsequently induces IL-17 production in activated T cells. The effects of PGE2 are mediated through the EP2/EP4 receptors on DCs. In vivo, we assessed the effects of PGE analogs in an experimental model for inflammatory bowel disease and found that the exacerbation of clinical symptoms and histopathology correlated with an increase in IL-23 and IL-17, a decrease in IL-12p35 expression in colon and mesenteric lymph nodes, and a substantial increase in the number of infiltrating neutrophils and of CD4+IL-17+ T cells in the colonic tissue. These studies suggest that high levels of PGE2 exacerbate the inflammatory process through the preferential expression and release of DC-derived IL-23 and the subsequent support of the autoreactive/inflammatory Th17 phenotype.

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IL23R Arg381Gln is associated with childhood onset inflammatory bowel disease in Scotland

Cited by 80 publications

References 15 publications

Inflammatory bowel disease: Genetic and epidemiologic considerations

Inflammatory bowel disease: Genetic and epidemiologic considerations

Detailed genetic characterization of the interleukin-23 receptor in psoriasis

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

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