Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021390 (inflammatory bowel disease)
 23,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The era of genome-wide association (GWA) scanning has shed new light on the genetic basis of common disease and nowhere is this better illustrated than Crohn's disease (CD). CD is a chronic debilitating inflammatory bowel disease characterized by stricturing and fistula formation. Mainstays of current therapy are immune suppression and surgery. The pathogenesis of CD is poorly understood, but it has long been recognized that both genetic susceptibility and bacterial antigens play important roles. A variety of intracellular bacteria have been postulated to trigger CD, but the evidence for any one organism is equivocal. The current consensus is that commensal gut bacteria provide the drive for CD-related inflammation. Three GWA scans undertaken in the last 6 months have identified 10 new loci demonstrating highly significant and replicated association with CD. Two of the strongest hits implicate genes IRGM and ATG16L1, which encode proteins thought to be critical to the autophagy pathway. The critical next step is functional characterization of the CD-associated genetic variants in IRGM and ATG16L. It seems highly plausible that variation in these genes holds the key to understanding exactly which bacteria drive the intestinal inflammation of CD and the mechanism by which they do this.
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PMID:Genome-wide association scanning highlights two autophagy genes, ATG16L1 and IRGM, as being significantly associated with Crohn's disease. 1792 95

The volume of research undertaken on the genetic susceptibility of inflammatory bowel disease (IBD) has been tremendous. Genome-wide linkage studies pointed towards more than 10 chromosomal regions and fine-mapping of these regions led to the identification of a number of genes, including CARD15 (NOD2), DLG5, OCTN1 and 2, TLR4 and CARD4 (NOD1). With the recent completion of the human genome project, whole genome association studies (WGAS) have now become possible and have identified additional genes (IL23R, IRGM, PTGER4, ATG16L1) for Crohn's disease and ulcerative colitis, that have subsequently been replicated. At present, the CARD15 gene is still the most understood susceptibility gene, explaining around 20% of the genetic predisposition to Crohn's disease. Prediction of disease phenotype and response to the main therapies has for many years been a dream for physicians treating IBD patients. Only now, we start to accumulate some evidence proving that genetic factors indeed influence both the clinical course of IBD patients and their likelihood of responding to certain therapies. In the coming years, we expect an exponential increase in the efforts devoted to research in this area. The optimal prediction of both disease behaviour and response to therapy might result from complex combinations of clinical, biochemical, serological and genetic factors.
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PMID:The role of genetics in inflammatory bowel disease. 1847 63

Genome-wide association studies have identified PHOX2B, FAM92B, IRGM and NCF4 as candidate susceptibility factors for ileal Crohn's disease (CD). Here we sought to determine whether these genes were also associated with ileal CD in New Zealand Caucasians, as well as with ileocolonic CD, colonic CD and ulcerative colitis (UC). A total of 507 CD patients, 475 UC patients and 576 controls were genotyped for the single nucleotide polymorphisms rs16853571 (PHOX2B), rs4821544 (NCF4), rs13361189 and rs4958847 (IRGM), and rs8050910 (FAM92B). NCF4 and IRGM were significantly associated with ileal CD (P-value(rs4821544)=0.0090, odds ratio (OR)=1.425, 95% confidence interval (CI): 1.092-1.859; P-value(rs13361189)=0.0017, OR=1.942, 95% CI: 1.274-2.959; P-value(rs4958847)=0.0022, OR=1.767, 95% CI: 1.224-2.558), but not with other forms of inflammatory bowel disease (IBD). No association of PHOX2B or FAM92B with IBD was detected. Our study has demonstrated that IRGM and NCF4 are ileal-specific CD susceptibility factors in New Zealand Caucasians.
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PMID:Confirmation of association of IRGM and NCF4 with ileal Crohn's disease in a population-based cohort. 1858 Aug 84

Recent genome-wide association studies have linked polymorphisms in two atophagy genes, Atg16L1 and IRGM, with Crohn's Disease. Now, experiments with Atg16L1 transgenic mice indicate multiple roles for autophagy in inflammatory bowel disease via effects on Paneth cells, a runaway inflammasome, and the proinflammatory cytokine IL-1beta.
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PMID:Autophagy gives a nod and a wink to the inflammasome and Paneth cells in Crohn's disease. 1900 Aug 29

Inflammatory bowel disease (IBD) consists of two main disorders, ulcerative colitis and Crohn's disease, that cause chronic, recurrent inflammation of the intestine. An inappropriate immune response to the enteric ecosystem has been postulated to cause IBD. Genomewide association studies provide the information of diverse genetic variations and susceptibilities to patients with IBD. Through the application of these studies, the pathogenesis of IBD may result in part from genetic abnormalities that regulate epithelial barrier function and innate and adaptive immune responses. Crohn's disease shows strong association with CARD15, ATG15L1, and IRGM, which are involved in the innate immunity. In the adaptive immune response, IL23R, MST1, IL12B, and STAT3 polymorphisms are associated with Crohn's disease and ulcerative colitis. Current pharmacologic treatment of IBD, including 5-aminosalycylate, steroids, and immunomodulator therapy, are mainly aimed at suppressing inflammation non-specifically, except biologic therapies such as anti-tumor necrosis factor molecule, which block specific proinflammatory molecules. For nutritional issues in IBD, the mainstay of therapy has been supportive, with particular attention paid to the prevention, recognition, and therapy of nutritional deficiencies, and individual outcomes to specific dietary factors have been controversial. Parenteral nutritional support and exclusionary diets have been investigated and are not the subject of this review. The emerging concepts of nutrition-gene interaction gave birth to unique scientific fields, nutrigenetics and nutrigenomics. These studies provide information about 1) the genetic variability that induces an individual's response to nutrition according to particular states of health and disease and 2) changes in gene expression that develop as a result of nutrition-gene interaction. For IBD, the role of diet in the regulation of the immune response against gut flora is the subject of current intensive evaluation. These approaches may lead clinicians to derive a personalized nutritional prescription based on individual genetic variations and may result in a significant impact on IBD treatment.
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PMID:DNA-driven nutritional therapy of inflammatory bowel disease. 1964 22

Evidence about the presence of susceptibility factors shared among different autoimmune diseases is increasing. Based on this idea, NKX2-3, ATG16L1, and IRGM which are well-established inflammatory bowel disease risk factors, could be new celiac disease (CD) candidate genes. NKX2-3 encodes a transcription factor that in mice seems to be involved in gut development. The ATG16L1 and IRGM genes act in autophagy, a process related to innate and adaptive immunity. We aimed to study the implication of five polymorphisms in these genes in CD susceptibility: rs10883365 and rs888208 in the NKX2-3 gene, rs2241880 in ATG16L1, and rs10065172 and rs4958847 in IRGM. Association studies were performed using 725 Spanish CD patients and 956 ethnically matched healthy controls, as well as 309 parent-child trios. Genetic frequencies were compared with the chi(2) test and the familial study used the transmission disequilibrium test. Differences between CD patients and controls did not reach significance when genotypic and allelic frequencies were compared. No differential transmission of alleles or haplotypes from heterozygous parents to affected children was observed in the familial study. In conclusion, no evidence of association with CD has been reported for the Crohn's disease susceptibility polymorphisms studied in the NKX2-3, ATG16L1, and IRGM genes.
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PMID:Lack of association of NKX2-3, IRGM, and ATG16L1 inflammatory bowel disease susceptibility variants with celiac disease. 1968 22

Epidemiological data, detailed molecular studies and recent genome-wide association studies strongly suggest that ulcerative colitis (UC) and Crohn's disease (CD) are related polygenic diseases that share some susceptibility loci, but differ at others. To date, there are more than 50 confirmed inflammatory bowel disease genes/loci, a number that is widely anticipated to at least double in the next 2 years. Germline variation in IL23R, IL12B, JAK2 and STAT3 is associated with inflammatory bowel disease susceptibility, consistent with the newly described role for IL23 signaling and Th17 cells in disease pathogenesis. Several genes involved in different aspects of bacterial handling are defective only in CD, including NOD2 and the autophagy genes ATG16L1 and IRGM. IL10 and ECM1 are associated with UC, while inherited variation at the HLA region is related to an inflammatory colonic phenotype. The application of genome-wide association studies to inflammatory bowel disease has been successful in defining the genetic architecture of CD and UC and in delivering genuinely novel and important insights into disease pathogenesis. This has unearthed a plethora of attractive targets for the development of future therapeutics. Insights into the natural history of these complex diseases will follow and may enable appropriate patient selection for early aggressive therapy with the view to modifying the disease course.
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PMID:Genetics of inflammatory bowel disease: implications for disease pathogenesis and natural history. 1981 73

Twin studies and large-scale population studies have confirmed an increased sibling risk for both Crohn's disease (CD) and ulcerative colitis (UC). Unlike single gene disorders, CD and UC are thought to result from a complex interplay of multiple genes and environmental factors. The confirmation of CARD15/NOD2 as a CD susceptibility gene in the late 1990s caused much excitement in the field of complex diseases in general and since then, the rapid rate of progress in molecular genetics, with the advent of large-scale affordable genotyping techniques, has resulted in large collaborations and the identification of over 30 inflammatory bowel disease (IBD)-associated genes. In particular, the importance of the innate immune system has been reaffirmed with the identification of IRGM and ATG16L1 genes in the autophagy pathway as CD susceptibility genes. Disturbance in the adaptive immune system, in particular the IL-23/Th17 axis, has also shown to be of importance for IBD overall. In this era of genome-wide association studies it may be possible to, at last, identify the multiple genes involved in IBD and thus improve our understanding of the genotype-phenotype correlation and improve treatment.
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PMID:The genetic basis of inflammatory bowel disease. 1989 57

The genetic component of Inflammatory Bowel Diseases is among the best known for complex genetic disorders. If the functional candidate gene approach was rarely fruitful in the past, genome-wide scans allowed finding several susceptibility genes for Crohn disease including NOD2, IL23R, ATG16L1, IRGM, TNFSF15, a region close to PTGER4, PTPN2, PTPN22, NKX2-3 and many others. Only one gene, ECM1, has been reported for ulcerative colitis alone. We now need to further explore these new genes before to understand their biological role. However they clearly demonstrate the importance of innate immunity and autophagy for Crohn's disease and of the TH-17 differentiation for ulcerative colitis, Crohn's disease and other inflammatory disorders.
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PMID:Inflammatory Bowel Diseases: the genetic revolution. 2011 35

Previous European studies suggest NOD2/CARD15 and interleukin-23 receptor (IL-23R) donor or recipient variants are associated with adverse clinical outcomes in allogeneic hematopoietic stem cell transplantation. We reexamined these findings as well as the role of another inflammatory bowel disease (IBD) susceptibility gene (immunity-related GTPase family, M [IRGM]) on transplantation outcomes in 390 US patients and their matched unrelated donors, accrued between 1995 and 2004. Patients received T-replete grafts with mostly myeloablative conditioning regimens. Multivariate analyses were performed for overall survival, disease-free survival, transplantation-related mortality, relapse, and acute and chronic graft-versus-host disease. Of 390 pairs, NOD2/CARD15 variant single nucleotide polymorphisms (SNPs) were found in 14% of donors and 17% of recipients. In 3% both donor and recipient had a mutant SNP. Thirteen percent of donors and 16% of recipients had variant IL23R SNPs, with 3% having both donor and recipient variants. Twenty-three percent of both donors and recipients had variant IRGM SNPs. None of the 3 IBD-associated alleles showed a statistically significant association with any adverse clinical outcomes. Our results do not support an association between the 3 IBD-associated SNPs and adverse outcomes after matched unrelated donor hematopoietic cell transplantations in US patients.
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PMID:Insufficient evidence for association of NOD2/CARD15 or other inflammatory bowel disease-associated markers on GVHD incidence or other adverse outcomes in T-replete, unrelated donor transplantation. 2017 49


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