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)

The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.
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PMID:A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. 1713 88

We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10(-10)) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.
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PMID:Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. 1743 56

To identify novel susceptibility loci for Crohn disease (CD), we undertook a genome-wide association study with more than 300,000 SNPs characterized in 547 patients and 928 controls. We found three chromosome regions that provided evidence of disease association with p-values between 10(-6) and 10(-9). Two of these (IL23R on Chromosome 1 and CARD15 on Chromosome 16) correspond to genes previously reported to be associated with CD. In addition, a 250-kb region of Chromosome 5p13.1 was found to contain multiple markers with strongly suggestive evidence of disease association (including four markers with p < 10(-7)). We replicated the results for 5p13.1 by studying 1,266 additional CD patients, 559 additional controls, and 428 trios. Significant evidence of association (p < 4 x 10(-4)) was found in case/control comparisons with the replication data, while associated alleles were over-transmitted to affected offspring (p < 0.05), thus confirming that the 5p13.1 locus contributes to CD susceptibility. The CD-associated 250-kb region was saturated with 111 SNP markers. Haplotype analysis supports a complex locus architecture with multiple variants contributing to disease susceptibility. The novel 5p13.1 CD locus is contained within a 1.25-Mb gene desert. We present evidence that disease-associated alleles correlate with quantitative expression levels of the prostaglandin receptor EP4, PTGER4, the gene that resides closest to the associated region. Our results identify a major new susceptibility locus for CD, and suggest that genetic variants associated with disease risk at this locus could modulate cis-acting regulatory elements of PTGER4.
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PMID:Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. 1744 42

Inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis are characterised by chronic transmural, segmental and typically granulomatous inflammation of the gut. Each has a peak age of onset in the second to fourth decades of life and prevalence has been increasing significantly in both Western countries and Japan over the last decade, while their pathogenesis remains largely unknown. Recently, positive association of CD with the variants in interleukin 23 receptor (IL23R), autophagy-related 16-like 1 (ATG16L1) genes and chromosome 5p13.1 locus was reported through genome-wide association studies which are now recognised as a robust tool for the identification of susceptibility genes for complex diseases. To examine an association of reported susceptible variants in the three loci with Japanese CD patients, a total of 484 CD patients and 439 controls were genotyped. No evidence of positive association for any of these loci with CD was found in the Japanese population, even after clinically stratified subgroups of CD were used. Our result revealed a distinct ethnic difference of genetic background of CD that we reported previously in other genes between Japanese and Caucasian populations. Further genetic studies are required to confirm our findings with ethnically divergent populations.
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PMID:Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn's disease in Japanese patients. 1753 74

Psoriasis is an inflammatory skin disorder that is inherited as a multifactorial trait. Genetic analyses have repeatedly identified a primary disease susceptibility locus lying within the major histocompatibility complex (MHC), on chromosome 6p21. A small number of non-MHC susceptibility loci have also been identified. These regions tend to overlap with susceptibility intervals for Crohn's disease and atopic dermatitis, suggesting the possibility that genetic variants affecting inflammatory pathways may contribute to the pathogenesis of multiple disorders. Here, we report a genetic analysis of the interleukin 23 receptor gene (IL23R), which was recently identified as a susceptibility determinant for Crohn's disease. We initially examined the results of a whole-genome association scan, carried out on 318 cases and 288 controls. We observed a significant increase of a non-synonymous substitution (p.Arg381Gln) among controls (P = 0.00036). We validated this finding by extending our cohort to include a further 519 cases and 528 controls. In the overall sample, the frequency of the 381Gln allele was 3.6% in cases and 7% in controls, yielding a P value of 0.00014. Next, we examined genetic variation at the IL12RB1, IL23A and IL12B genes, respectively, encoding the second subunit of the IL23R receptor and the two subunits of its ligand. This analysis identified independent associations for IL12B SNPs rs10045431 (P value for the extended dataset = 0.0001) and rs3212227 (P = 0.036). Altogether, these findings indicate that genes participating in IL23 signalling play a significant role in the pathogenesis of chronic epithelial inflammation.
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PMID:Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis. 1758 57

Pediatric-onset inflammatory bowel disease (IBD) is characterized by distinct phenotypic differences compared to adult-onset IBD. This raises the question whether early (pediatric) onset IBD represents the same disease process occurring in adults but merely at an earlier age or does IBD in children have a very different etiology and pathogenesis but with the same clinical presentation as adults. The use of techniques such as whole genome association studies to perform broad, unbiased screening for the contributions of common genetic variations to complex disease has rapidly assisted in the identification of several novel susceptibility loci associated with pediatric-onset Crohn's disease such as IL23R and ATG16L1. These genes join the already confirmed IBD susceptibility genes such as NOD2/CARD15, IBD5, and DLG5. Therefore, there is hope that advances in the field of clinical and molecular genetics will assist in answering the fundamental question of whether pediatric IBD has a different etiology and pathogenesis compared to adult IBD. This review examines the current status of clinical and molecular genetics of pediatric IBD, and highlights the differences between pediatric and adult IBD in disease phenotypes and genotypes. Finally, the future directions of genetic investigations in pediatric IBD are discussed.
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PMID:Pediatric inflammatory bowel disease: clinical and molecular genetics. 1760 Mar 81

Genome-wide association (GWA) studies offer a powerful unbiased method for the identification of multiple susceptibility genes for complex diseases. Here we report the results of a GWA study for Crohn's disease (CD) using family trios from the Quebec Founder Population (QFP). Haplotype-based association analyses identified multiple regions associated with the disease that met the criteria for genome-wide significance, with many containing a gene whose function appears relevant to CD. A proportion of these were replicated in two independent German Caucasian samples, including the established CD loci NOD2 and IBD5. The recently described IL23R locus was also identified and replicated. For this region, multiple individuals with all major haplotypes in the QFP were sequenced and extensive fine mapping performed to identify risk and protective alleles. Several additional loci, including a region on 3p21 containing several plausible candidate genes, a region near JAKMIP1 on 4p16.1, and two larger regions on chromosome 17 were replicated. Together with previously published loci, the spectrum of CD genes identified to date involves biochemical networks that affect epithelial defense mechanisms, innate and adaptive immune response, and the repair or remodeling of tissue.
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PMID:Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci. 1780 89

Nutrigenomics has the potential to tailor diets to optimize health, based on knowledge of key genetic polymorphisms. Identification of candidate genes is often based on a priori knowledge of disease processes. However, genome-wide association methods are not only validating previously identified genes and polymorphisms, but also revealing new gene-disease associations not anticipated from prior knowledge. In Crohn's disease (CD), such studies not only confirm the importance of caspase-activated recruitment domain 15 and major histocompatibility complex II molecules, but also reveal strong associations with the proinflammatory cytokine interleukin-23 receptor and autophagy-related 16-like gene. Genes identified to date in CD can be linked into two interrelated pathways: receptor-mediated cytokine induction or autophagocytosis. New genomic technologies need to be matched with innovative methodologies to characterize the likely impact of foods and to take the field to another dimension of value for human diet development and optimized health.
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PMID:Nutrigenomics in the whole-genome scanning era: Crohn's disease as example. 1792 30

Psoriasis is a common inflammatory and hyperproliferative skin disease with a multifactorial genetic basis. A recent study reported that psoriasis was associated with the IL12B haplotype rs3212227 (3'-untranslated region)-rs6887695 (60 kb, 5') and the IL23R haplotype rs7530511 (L310P)-rs11209026 (Q381R). We examined these four single-nucleotide polymorphisms (SNPs) for association with psoriasis in two groups of North American and German Caucasians: (1) 1,810 cases and 2,522 controls; and (2) 509 pedigrees. Both IL12B markers showed highly significant association with psoriasis in the case-control (rs3212227, odds ratio (OR)=1.62, P=1.7 x 10(-15); rs6887695, OR=1.49, P=2.7 x 10(-15)) and in the family-based analysis (rs3212227, P=2.2 x 10(-3); rs6887695, P=1.7 x 10(-3)). The IL23R SNPs also showed significant association in the cases and controls (rs7530511, OR=1.22, P=3.9 x 10(-3); rs11209026, OR=1.40, P=3.8 x 10(-4)). For both genes, common risk haplotypes were identified whose statistical significance approached (IL23R) or exceeded (IL12B) genome-wide criteria. We found no statistical evidence for interactions of these haplotypes with HLA-Cw6. Our results confirm associations between IL12B and IL23R and psoriasis in Caucasians, and provide a genetic basis for the clinical association between psoriasis and Crohn's disease.
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PMID:Polymorphisms of the IL12B and IL23R genes are associated with psoriasis. 1821 80

Inflammatory bowel disease constitutes two related clinical entities, Crohn's disease (CD) and ulcerative colitis (UC), both of which have increased in prevalence over the last decade. Family and twin studies have strongly indicated that genetic factors play a large role in an individual's risk of developing inflammatory bowel disease. Despite this, it has proven difficult to isolate disease genes that confer susceptibility to this disease using classical candidate gene and linkage approaches, with the notable exception of the isolation of the caspase recruitment domain family, member 15 (CARD15) gene. However, over the last 2 years, genome-wide association (GWA) studies have become feasible, where modern high-throughput single nucleotide polymorphism (SNP) genotyping technologies can be applied to large and comprehensively phenotyped patient cohorts. Such approaches have enabled scientists to robustly associate specific variants with many complex diseases, including age-related macular degeneration, Type 2 diabetes, breast cancer and asthma. In the inflammatory bowel disease field, positive associations with CD and UC coming from GWA studies have been reported for an ever increasing number of genes. The most consistently and strongly associated variants have been in the CARD15, the interleukin 23 receptor (IL23R) and autophagy-related 16-like 1 (ATG16L1) genes. With respect to ATG16L1, the G allele of SNP rs2241880 has been shown in multiple association studies to confer strong risk for CD, although its association with UC remains more debatable. This SNP is in fact a common coding variant, specifically a threonine-to-alanine substitution at amino acid position 300 of the ATG16L1 protein (T300A), and appears to account for all of the disease risk conferred by this locus. This review addresses recent advances in GWA studies of inflammatory bowel disease, with specific focus on the growing evidence of the ATG16L1 gene's role in CD and how its protein product operating within the autophagic pathway makes autophagy an attractive therapeutic target for this debilitating disorder.
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PMID:Classification of genetic profiles of Crohn's disease: a focus on the ATG16L1 gene. 1836 6


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