Genetic Analysis of Innate Immunity in Crohn's Disease and Ulcerative Colitis Identifies Two Susceptibility Loci Harboring CARD9 and IL18RAP

Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
The American Journal of Human Genetics (Impact Factor: 10.93). 06/2008; 82(5). DOI: 10.1016/j.ajhg.2008.03.016
Source: OAI

ABSTRACT The two main phenotypes of inflammatory bowel disease (IBD)--Crohn's disease (CD) and ulcerative colitis (UC)--are chronic intestinal inflammatory disorders with a complex genetic background. Using a three-stage design, we performed a functional candidate-gene analysis of innate immune pathway in IBD. In phase I, we typed 354 SNPs from 85 innate immunity genes in 520 Dutch IBD patients (284 CD, 236 UC) and 808 controls. In phase II, ten autosomal SNPs showing association at p < 0.006 in phase I were replicated in a second cohort of 545 IBD patients (326 CD, 219 UC) and 360 controls. In phase III, four SNPs with p < 0.01 in the combined phase I and phase II analysis were genotyped in an additional 786 IBD samples (452 CD, 334 UC) and 768 independent controls. Joint analysis of 1851 IBD patients (1062 CD, 789 UC) and 1936 controls demonstrated strong association to the IL18RAP rs917997 SNP for both CD and UC (p(IBD) 1.9 x 10(-8); OR 1.35). Association in CD is independently supported by the Crohn's disease dataset of the Wellcome Trust Case Control Consortium (imputed SNP rs917997, p = 9.19 x 10(-4)). In addition, an association of the CARD9 rs10870077 SNP to CD and UC was observed (p(IBD) = 3.25 x 10(-5); OR 1.21). Both genes are located in extended haplotype blocks on 2q11-2q12 and 9q34.3, respectively. Our results indicate two IBD loci and further support the importance of the innate immune system in the predisposition to both CD and UC.

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Available from: Ad A van Bodegraven, Sep 28, 2015
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    • "The association between NOD2 and CARD9 was enhanced by the presence of RIP2 in both over-expression and endogenous systems [17]. The relationship between CARD9 and NOD2 is particularly intriguing as the genes for both these proteins contain polymorphisms influencing susceptibility to Crohn's Disease in humans [18] [19]. Multiprotein complexes play a key role in innate immune signalling . "
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    ABSTRACT: NOD2 activation by muramyl dipeptide causes a proinflammatory immune response in which the adaptor protein CARD9 works synergistically with NOD2 to drive p38 and c-Jun N-terminal kinase (JNK) signalling. To date the nature of the interaction between NOD2 and CARD9 remains undetermined. Here we show that this interaction is not mediated by the CARDs of NOD2 and CARD9 as previously suggested, but that NOD2 possesses two interaction sites for CARD9; one in the CARD-NACHT linker and one in the NACHT itself. Structured summary of protein interactions: NOD2 physically interacts with CARD9 by anti tag coimmunoprecipitation (View interaction) (C) 2014 The Authors. Published by Elsevier B.V.
    FEBS Letters 06/2014; 588(17). DOI:10.1016/j.febslet.2014.06.035 · 3.17 Impact Factor
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    • "In the gut-microbiota interplay related to IBD pathogenesis, several previous findings point towards the potential role of the inflammasome in the development of chronic intestinal inflammation. The first evidence refers to the upregulation of inflammatory cytokines IL-1β and IL-18 in active IBD, and the discovery of IL-18 gene polymorphisms associated with CD [31–33]. The second is the presence of a dysregulated IL-1β production linked to CD and the association between the NLRP3 inflammasome and three rare autoinflammatory chronic disorders treated with Canakinumab, a human monoclonal antibody targeted at IL-1β [22, 31, 34, 35]. "
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    ABSTRACT: The activation of specific cytosolic pathogen recognition receptors, the nucleotide-binding-oligomerization-domain- (NOD-) like receptors (NLRs), leads to the assembly of the inflammasome, a multimeric complex platform that activates caspase-1. The caspase-1 pathway leads to the upregulation of important cytokines from the interleukin (IL)-1 family, IL-1 β , and IL-18, with subsequent activation of the innate immune response. In this review, we discuss the molecular structure, the mechanisms behind the inflammasome activation, and its possible role in the pathogenesis of inflammatory bowel diseases and intestinal cancer. Here, we show that the available data points towards the importance of the inflammasome in the innate intestinal immune response, being the complex involved in the maintenance of intestinal homeostasis, correct intestinal barrier function and efficient elimination of invading pathogens.
    Mediators of Inflammation 03/2013; 2013(6100):654963. DOI:10.1155/2013/654963 · 3.24 Impact Factor
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    • "Closer inspection revealed several SNPs in the vicinity of -- but not within -- CARD9 that were strongly associated with the expression of this gene. CARD9 has previously been implicated in Crohn’s disease, although the association was not replicated in the WTCCC study (17). "
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    ABSTRACT: Expression quantitative trait loci (eQTL), or genetic variants associated with changes in gene expression, have the potential to assist in interpreting results of genome-wide association studies (GWAS). eQTLs also have varying degrees of tissue specificity. By correlating the statistical significance of eQTLs mapped in various tissue types to their odds ratios reported in a large GWAS by the Wellcome Trust Case Control Consortium (WTCCC), we discovered that there is a significant association between diseases studied genetically and their relevant tissues. This suggests that eQTL data sets can be used to determine tissues that play a role in the pathogenesis of a disease, thereby highlighting these tissue types for further post-GWAS functional studies.
    03/2012; 2012:35-41.
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