Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0010346 (Crohn's disease)
 21,615 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
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PMID:Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. 1138 52

Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies, but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease.
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PMID:A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. 1138 52

Background Genetic predisposition to inflammatory bowel disease (IBD) has been shown by epidemiological and linkage studies. Genetic linkage of IBD to chromosome 16 has been previously observed and replicated in independent populations. The recently identified NOD2 gene is a good positional and functional candidate gene since it is located in the region of linkage on chromosome 16q12, and activates nuclear factor (NF) kappaB in response to bacterial lipopolysaccharides. Methods We sequenced the coding region of the NOD2 gene and genotyped an insertion polymorphism affecting the leucine-rich region of the protein product in 512 individuals with IBD from 309 German or British families, 369 German trios (ie, German patients with sporadic IBD and their unaffected parents), and 272 normal controls. We then tested for association with Crohn's disease and ulcerative colitis. Findings Family-based association analyses were consistently positive in 95 British and 99 German affected sibling pairs with Crohn's disease (combined p<0.0001); the association was confirmed in the 304 German trios with Crohn's disease. No association was seen in the 115 sibling pairs and 65 trios with ulcerative colitis. The genotype-specific disease risks conferred by heterozygous and homozygous mutant genotypes were 2.6 (95% CI 1.5-4.5) and 42.1 (4.3-infinity), respectively. Interpretation The insertion mutation in the NOD2 gene confers a substantially increased susceptibility to Crohn's disease but not to ulcerative colitis.
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PMID:Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. 1142 8

We have identified three missense mutations in the nucleotide-binding domain (NBD) of CARD15/NOD2 in four French and German families with Blau syndrome. Our findings indicate that, in addition to Crohn disease, CARD15 is involved in the susceptibility to a second granulomatous disorder.
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PMID:CARD15 mutations in Blau syndrome. 1152 84

This article reviews a selection of 50 papers on inflammatory bowel disease published between April 2000 and June 2001. The new information summarized here includes: the discovery of the association of the NOD2 gene with Crohn's disease; the role of bacteria and the modulating effects of probiotics; the inverse association of appendectomy and ulcerative colitis; progress in imaging based on magnetic resonance imaging and leukocyte scintigraphy; assessment of the value of anti-Saccharomyces cerevisiae antibodies in the screening of inflammatory bowel disease and differentiation between ulcerative colitis and Crohn's disease; and risk factors and management of dysplasia and cancer. This article does not review all therapeutic aspects, but focuses on smoking cessation; anti-tumor necrosis factor antibody treatments; the usefulness of measuring erythrocyte 6-thioguanine metabolite levels to optimize purine analogue therapy; strictureplasty; and the long-term results of ileoanal anastomosis.
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PMID:Inflammatory bowel disease. 1177 31

CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.
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PMID:CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. 1187 55

An insertion mutation at nucleotide 3020 (3020insC) in the CARD15 gene, originally reported as NOD2, has been strongly associated with Crohn's disease. The CARD15 G2722C missense mutation was also shown to be associated with this disease. We studied 130 Dutch Crohn's disease patients, with a median follow up of 9.2 years, in relation to the Vienna classification, and 152 ethnically matched healthy controls. We confirm reports that the CARD15 3020insC mutation increases the susceptibility to Crohn's disease, but we do not confirm this relationship for CARD15 G2722C. Our findings suggest that these mutations are not a marker of a particular form of Crohn's disease according to the Vienna classification. Whether the CARD153020insC and CARD15 G2722C mutations are responsible for a different etiopathogenic mechanism in a subgroup of patients remains to be studied.
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PMID:CARD15 gene and the classification of Crohn's disease. 1197 92

Tumour necrosis factor-alpha (TNF) expression is increased in inflammatory bowel disease (IBD), and TNF maps to the IBD3 susceptibility locus. Transmission disequilibrium and case-control analyses, in two independent Caucasian cohorts, showed a novel association of the TNF(-857C) promoter polymorphism with IBD (overall P=0.001 in 587 IBD families). Further genetic associations of TNF(-857C) with IBD sub-phenotypes were seen for ulcerative colitis and for Crohn's disease, but only in patients not carrying common NOD2 mutations. The genetic data suggest a recessive model of inheritance, and we observed ex vivo lipopolysaccharide-stimulated whole-blood TNF production to be higher in healthy TNF(-857C) homozygotes. We show the transcription factor OCT1 binds TNF(-857T) but not TNF(-857C), and interacts in vitro and in vivo with the pro-inflammatory NF(-kappa)B transcription factor p65 subunit at an adjacent binding site. Detailed functional analyses of these interactions in gut macrophages, in addition to further genetic mapping of this gene-dense region, will be critical to understand the significance of the observed association of TNF(-857C) with IBD.
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PMID:Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B transcription factors. 1201 9

Inflammatory bowel disease (IBD) is a multifactorial disorder, with both genetic and environmental factors contributing to the two clinical phenotypes of Crohn's disease (CD) and ulcerative colitis (UC). The underlying genetic model is thought to involve multiple genes with complex interactions between disease loci, and the NOD2 gene on chromosome 16 has recently been identified as a CD susceptibility locus. Several genome-wide linkage studies have identified candidate regions, but there has been little replication across studies. Here we investigate the role of sex-specific loci in susceptibility to IBD. Linkage data from our previously reported genome search and follow-up study were stratified by the sex of the affected sib pair. Non-parametric linkage analysis was performed using Genehunter Plus. Simulation studies were used to assess the significance of differences in LOD scores between male and female families for each chromosome. Several regions of sex-specific linkage were identified, including existing and novel candidate loci. The major histocompatibility region on chromosome 6p, referred to as IBD3, showed evidence of male-specific linkage with a maximum LOD score of 5.9 in both CD and UC male-affected families. Regions on chromosomes 11, 14 and 18 showed strong evidence of linkage in male-affected families but not in female-affected families. No evidence of sex-specific linkage was found in the IBD1 or IBD2 candidate regions of chromosomes 16 and 12. The existence of sex-specific linkage is further evidence of the complex mechanisms involved in IBD and will facilitate future studies to identify susceptibility genes.
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PMID:Sex stratification of an inflammatory bowel disease genome search shows male-specific linkage to the HLA region of chromosome 6. 1203 34

Spondyloarthropathies are a cluster of interrelated and overlapping chronic inflammatory rheumatic diseases that primarily include ankylosing spondylitis, reactive arthritis, and the arthritis associated with psoriasis and inflammatory bowel diseases. The primary pathologic sites are the entheses (the sites of bony insertion of ligaments and tendons); the axial skeleton, including the sacroiliac joints; the limb joints; and some nonarticular structures, such as the gut, skin, eye, and aortic valve. Although spondyloarthropathies are not associated with rheumatoid factor, they show a strong association with HLA-B27; however, this association varies markedly among various spondyloarthropathies and among ethnic groups. The most widely used classification criterion, from the European Spondyloarthropathy Study Group, encompasses the currently recognized wider disease spectrum, with a sensitivity and specificity that generally exceed 85%. Spondyloarthropathies occur in genetically predisposed persons and are triggered by environmental factors, but the cellular and molecular mechanisms of inflammation are not yet fully understood. Chlamydial and many enterobacterial infections can trigger reactive arthritis, but an infectious trigger for ankylosing spondylitis has not yet been established. HLA-B27 itself is involved in enhancing genetic susceptibility, but the underlying molecular basis is still unknown; additional genes include the putative susceptibility genes for Crohn disease, ulcerative colitis, and psoriasis. A specific susceptibility gene for Crohn disease, NOD2, is located on chromosome 16q12, and one of the candidate genes for psoriasis, PSORS1, has been mapped to a 60-kb fragment on chromosome 6p, which is telomeric to the HLA-C locus. This paper reviews the efficacy of anti-tumor necrosis factor-alpha therapy and other therapeutic advances.
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PMID:Update on spondyloarthropathies. 1206 64


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