Diverse effects of the CARD15 and IBD5 loci on clinical phenotype in 630 patients with Crohn's disease
Genetic variants at the CARD15 and IBD5 loci are strongly associated with Crohn's disease (CD), but evidence of the effect of these variants on the clinical expression of CD is conflicting and has often been hampered by small sample sizes. We studied 630 well-characterized patients to clarify the genotype/phenotype relationship in CD.
Patients and healthy controls were genotyped for three common mutations in CARD15 and a marker of the IBD5 risk haplotype. Allele frequencies were compared between phenotypic subgroups using chi2 or Fisher's exact tests. Genotype/phenotype analysis was carried out using multinomial logistic regression modelling allowing for adjustment for correlated or confounding factors.
The mean age at diagnosis was significantly lower in carriers of the CARD15 or IBD5 risk alleles. After correction for age and smoking, CARD15 mutations were strongly associated with both ileal disease (P=8.8 x 10(-6)) and stenotic disease (P=0.003), but the association with stenotic disease appeared to be due to a confounding effect with ileal disease. CARD15 mutations were also associated with the presence of granulomas (P=5.7 x 10(-5)), which remained significant after adjustment for age at diagnosis and disease location (P=0.0047). The IBD5 risk haplotype frequency was significantly elevated in cases with perianal disease (P=0.028) and axial spondyloarthropathy (P=0.012).
Genetic variants at the CARD15 and IBD5 loci have diverse effects on clinical expression in CD. CARD15 mutations are significantly correlated with the presence of granulomas.
Available from: John C Whittaker
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ABSTRACT: There has been considerable recent success in the detection of gene-disease associations. We consider here the development of tools that facilitate the more detailed characterization of the effect of a genetic variant on disease. We replace the simplistic classification of individuals according to a single binary disease indicator with classification according to a number of subphenotypes. This more accurately reflects the underlying biological complexity of the disease process, but it poses additional analytical difficulties. Notably, the subphenotypes that make up a particular disease are typically highly associated, and it becomes difficult to distinguish which genes might be causing which subphenotypes. Such problems arise in many complex diseases. Here, we concentrate on an application to Crohn disease (CD). We consider this problem as one of model selection based upon log-linear models, fitted in a Bayesian framework via reversible-jump Metropolis-Hastings approach. We evaluate the performance of our suggested approach with a simple simulation study and then apply the method to a real data example in CD, revealing a sparse disease structure. Most notably, the associated NOD2.908G-->R mutation appears to be directly related to more severe disease behaviors, whereas the other two associated NOD2 variants, 1007L-->FS and 702R-->W, are more generally related to disease in the small bowel (ileum and jejenum). The ATG16L1.300T-->A variant appears to be directly associated with only disease of the small bowel.
The American Journal of Human Genetics 02/2009; 84(2):178-87. DOI:10.1016/j.ajhg.2008.12.015 · 10.93 Impact Factor
Available from: Mark D Fielder
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ABSTRACT: Crohn's disease is suggested to result from a microbially triggered immune-mediated autoimmune process, involving mainly the terminal ileum and ileo-caecal junction. Klebsiella pneumoniae shares certain molecular structures present in pullulanase pulA and pulD secretion enzymes with various self-antigens present in collagens and HLA-B27 molecules, respectively. A link exists between high dietary starch intake and the growth of intestinal microflora, involving especially Klebsiella microbes. Increased exposure to Klebsiella in the gut as the result of high starch intake would lead to high production of antiKlebsiella antibodies as well as autoantibodies to the cross-reactive self-antigens with the resultant inflammation at the pathological sites. Eradication of these microbes from the gut in patients with Crohn's disease with the use of low-starch diet and antibacterial agents as well as immunomodulatory measures could be beneficial in the management of this disease.
European journal of gastroenterology & hepatology 05/2009; 21(8):843-9. DOI:10.1097/MEG.0b013e328318ecde · 2.25 Impact Factor
Available from: Ailsa L Hart
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ABSTRACT: Perianal fistulation is a common complication of Crohn's disease (CD). Fistulating perianal CD appears to represent a distinct phenotype of CD, separate from luminal fistulating disease, with differing disease behavior and which often requires different therapeutic strategies. The etiology of Crohn's perianal fistulae appears to have genetic, microbiological, and immunological components. Relationships with IBD5, which codes for the organic/cation transporter and IRGM, important in the autophagy pathway, have been identified but further genetic associations remain elusive. The partially efficacious use of antibiotics and fecal diversion imply a microbiological component and, similarly, the partial efficacy of immunosuppressants and anti-tumor necrosis factor alpha (TNFalpha) treatments suggest not only that an immunological process is taking place, but also that microbiota alone cannot account for the pathogenesis. Recent work implicates failures in the tissue injury/repair process with myofibroblasts, matrix metalloproteinases, and an epithelial-to-mesenchymal transition being possible culprits. We examine these areas in a review of the current understanding of the etiology of Crohn's perianal fistulae.
Inflammatory Bowel Diseases 10/2009; 15(10):1591-8. DOI:10.1002/ibd.21026 · 4.46 Impact Factor
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