Genetics Of Inflammatory Bowel Disease Research Articles

Copper Metabolism Domain-Containing 1 Represses Genes That Promote Inflammation and Protects Mice From Colitis and Colitis-Associated Cancer

Activation of the transcription factor nuclear factor-κB (NF-κB) has been associated with the development of inflammatory bowel disease (IBD). Copper metabolism MURR1 domain containing 1 (COMMD1), a regulator of various transport pathways, has been shown to limit NF-κB activation. We investigated the roles of COMMD1 in the pathogenesis of colitis in mice and IBD in human beings. We created mice with a specific disruption of Commd1 in myeloid cells (Mye-knockout [K/O] mice); we analyzed immune cell populations and functions and expression of genes regulated by NF-κB. Sepsis was induced in Mye-K/O and wild-type mice by cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (LPS), colitis was induced by administration of dextran sodium sulfate, and colitis-associated cancer was induced by administration of dextran sodium sulfate and azoxymethane. We measured levels of COMMD1 messenger RNA in colon biopsy specimens from 29 patients with IBD and 16 patients without (controls), and validated findings in an independent cohort (17 patients with IBD and 22 controls). We searched for polymorphisms in or near COMMD1 that were associated with IBD using data from the International IBD Genetics Consortium and performed quantitative trait locus analysis. In comparing gene expression patterns between myeloid cells from Mye-K/O and wild-type mice, we found that COMMD1 represses expression of genes induced by LPS. Mye-K/O mice had more intense inflammatory responses to LPS and developed more severe sepsis and colitis, with greater mortality. More Mye-K/O mice with colitis developed colon dysplasia and tumors than wild-type mice. We observed a reduced expression of COMMD1 in colon biopsy specimens and circulating leukocytes from patients with IBD. We associated single-nucleotide variants near COMMD1 with reduced expression of the gene and linked them with increased risk for ulcerative colitis. Expression of COMMD1 bymyeloid cells has anti-inflammatory effects. Reduced expression or function of COMMD1 could be involved in the pathogenesis of IBD.

OP015 Gut homing markers in perianal Crohn's fistulae

OP015 Gut homing markers in perianal Crohn's fistulae

Characteristics of Japanese inflammatory bowel disease susceptibility loci

There are substantial differences in inflammatory bowel disease (IBD) genetics depending on the populations examined. We aimed to identify Japanese population-specific or true culprit susceptibility genes through a meta-analysis of past genetic studies of Japanese IBD. For this study, we reviewed 2,703 articles. The review process consisted of three screening stages: we initially searched for relevant studies and then relevant single nucleotide polymorphisms (SNPs). Finally, we adjusted them for the meta-analysis. To maximize our chances of analysis, we introduced proxy SNPs during the first stage. To minimize publication bias, no significant SNPs and solitary SNPs without pairs were combined to be reconsidered during the third stage. Additionally, two SNPs were newly genotyped. Finally, we conducted a meta-analysis of 37 published studies in 50 SNPs located at 22 loci corresponding to the total number of 4,853 Crohn's disease (CD), 5,612 ulcerative colitis (UC) patients, and 14,239 healthy controls. We confirmed that the NKX2-3 polymorphism is associated with common susceptibility to IBD and that HLA-DRB1*0450 alleles increase susceptibility to CD but reduce risk for UC while HLA-DRB1*1502 alleles increase susceptibility to UC but reduce CD risk. Moreover, we found individual disease risk loci: TNFSF15 and TNFα to CD and HLA-B*5201, and NFKBIL1 to UC. The genetic risk of HLA was substantially high (odds ratios ranged from 1.54 to 2.69) while that of common susceptibility loci to IBD was modest (odds ratio ranged from 1.13 to 1.24). Results indicate that Japanese IBD susceptibility loci identified by the meta-analysis are closely associated with the HLA regions.

Large Sample Size, Wide Variant Spectrum, and Advanced Machine-Learning Technique Boost Risk Prediction for Inflammatory Bowel Disease

We performed risk assessment for Crohn's disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory bowel disease (IBD), by using data from the International IBD Genetics Consortium's Immunochip project. This data set contains ~17,000 CD cases, ~13,000 UC cases, and ~22,000 controls from 15 European countries typed on the Immunochip. This custom chip provides a more comprehensive catalog of the most promising candidate variants by picking up the remaining common variants and certain rare variants that were missed in the first generation of GWAS. Given this unprecedented large sample size and wide variant spectrum, we employed the most recent machine-learning techniques to build optimal predictive models. Our final predictive models achieved areas under the curve (AUCs) of 0.86 and 0.83 for CD and UC, respectively, in an independent evaluation. To our knowledge, this is the best prediction performance ever reported for CD and UC to date.

Sequence Kernel Association Tests for the Combined Effect of Rare and Common Variants

Recent developments in sequencing technologies have made it possible to uncover both rare and common genetic variants. Genome-wide association studies (GWASs) can test for the effect of common variants, whereas sequence-based association studies can evaluate the cumulative effect of both rare and common variants on disease risk. Many groupwise association tests, including burden tests and variance-component tests, have been proposed for this purpose. Although such tests do not exclude common variants from their evaluation, they focus mostly on testing the effect of rare variants by upweighting rare-variant effects and downweighting common-variant effects and can therefore lose substantial power when both rare and common genetic variants in a region influence trait susceptibility. There is increasing evidence that the allelic spectrum of risk variants at a given locus might include novel, rare, low-frequency, and common genetic variants. Here, we introduce several sequence kernel association tests to evaluate the cumulative effect of rare and common variants. The proposed tests are computationally efficient and are applicable to both binary and continuous traits. Furthermore, they can readily combine GWAS and whole-exome-sequencing data on the same individuals, when available, and are also applicable to deep-resequencing data of GWAS loci. We evaluate these tests on data simulated under comprehensive scenarios and show that compared with the most commonly used tests, including the burden and variance-component tests, they can achieve substantial increases in power. We next show applications to sequencing studies for Crohn disease and autism spectrum disorders. The proposed tests have been incorporated into the software package SKAT.

973 Characterization of the Approximately 40,000 Patient Cohort of the International Inflammatory Bowel Disease (IBD) Genetics Consortium (IIBDGC)

973 Characterization of the Approximately 40,000 Patient Cohort of the International Inflammatory Bowel Disease (IBD) Genetics Consortium (IIBDGC)

Su1762 Clinical and Molecular Characterization of Medically Refractory Acute, Severe Colitis: Preliminary Results From the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) Immunochip Study

Clinical and molecular characterization of medically refractory acute, severe colitis : preliminary results from the international inflammatory bowel disease genetics consortium (IIBDGC) immunochip study

Genetics of inflammatory bowel disease: The state of play

Genetics of inflammatory bowel disease: The state of play

Genetics of inflammatory bowel diseases: A comparison between Western and Eastern perspectives

Inflammatory bowel disease (IBD) is a chronic relapsing intestinal inflammatory disorder with unidentified causes. Currently, studies indicate that IBD results from a complex interplay between various genetic and environmental factors that produce intestinal inflammation. However, these factors may differ for Asians and Caucasians. Thus, differences in epidemiology, genetic variants, and clinical phenotypes of IBD have been observed between the two populations. Understanding the discrepancies between data from populations with different genetic backgrounds and environmental factors may reveal fundamental aspects of IBD pathogenesis. Accordingly, this review will summarize the current knowledge of IBD genetics studied in Asian countries and compare it with that from Western countries, with special focus on innate bacterial sensing, autophagy, and the interleukin-23 receptor-T helper cell 17 pathway. The epigenetic nature of IBD pathogenesis as well as the pharmacogenetics related to the use of immunomodulators will also be briefly covered.

Genetics of inflammatory bowel diseases: a comparison between Western and Eastern perspectives

Genetics of inflammatory bowel diseases: a comparison between Western and Eastern perspectives

Relationship Between Proximal Crohn's Disease Location and Disease Behavior and Surgery: A Cross-Sectional Study of the IBD Genetics Consortium

In classifying Crohn's disease (CD) location, proximal (L4) disease includes esophagogastroduodenal (EGD) and jejunal disease. Our aim was to determine the influence of proximal disease on outcomes of behavior and need for surgery and to determine if there was significant clinical heterogeneity between EGD and jejunal disease. We performed a cross-sectional query of the NIDDK (National Institute of Diabetes and Digestive and Kidney Disease) Inflammatory Bowel Disease Genetics Consortium (IBDGC) database of patients with a confirmed diagnosis of CD and phenotyped per the IBDGC manual. Presence of any L4, L4-EGD, L4-jejunal, and non-L4 disease (L1-ileal, L2-colonic, and L3-ileocolonic) was compared with demographic features including age, race, ethnicity, smoking and inflammatory bowel disease (IBD) family history, diagnosis age, disease duration, clinical outcomes of inflammatory, stricturing or penetrating behavior, and CD abdominal surgeries. Univariate and multivariable analyses were performed with R. Among 2,105 patients with complete disease location data, 346 had L4 disease (175 L4-EGD, 115 L4-jejunal, and 56 EGD and jejunal) with 321 having concurrent L1-L3 disease. In all, 1,759 had only L1-L3 disease. L4 vs. non-L4 patients were more likely (P<0.001) to be younger at diagnosis, non-smokers, have coexisting ileal involvement, and have stricturing disease. L4-jejunal vs. L4-EGD patients were at least twice as likely (P<0.001) to have had ileal disease, stricturing behavior, and any or multiple abdominal surgeries. Remarkably, L4-jejunal patients had more (P<0.001) stricturing behavior and multiple abdominal surgeries than non-L4 ileal disease patients. Logistic regression showed stricturing risks were ileal (without proximal) site (odds ratio (OR) 3.18; 95% confidence interval 2.23-4.64), longer disease duration (OR 1.33/decade; 1.19-1.49), jejunal site (OR 2.90; 1.89-4.45), and older age at diagnosis (OR 1.21/decade; 1.10-1.34). Multiple surgery risks were disease duration (OR 3.74/decade; 3.05-4.64), penetrating disease (OR 2.60; 1.64-4.21), and jejunal site (OR 2.39; 1.36-4.20), with short duration from diagnosis to first surgery protective (OR 0.87/decade to first surgery; 0.84-0.90). Jejunal disease is a significantly greater risk factor for stricturing disease and multiple abdominal surgeries than either EGD or ileal (without proximal) disease. The Montreal site classification should be revised to include separate designations for jejunal and EGD disease.

Joseph B. Kirsner, MD, PhD, 1909-2012

Joseph B. Kirsner, MD, PhD, 1909-2012

Highlights in inflammatory bowel disease – from bench to bedside

Approximately 3.6 million people in Europe and the USA suffer from recurrent auto-immune-mediated inflammation of the gastrointestinal tract. Inflammatory bowel disease (IBD) comprises two entities: Crohn's disease (CD) and ulcerative colitis (UC). In the past, experimental studies (mostly in mice) have improved our understanding of the aberrant interaction between the intestinal microbiota and the immune system. The perturbed immune reaction in IBD exhibits specific and individual cytokine responses that distinguish the two variants. A deep understanding of the immunological response at every stage of the chronic disease enables the provision of modern, efficient medical treatment that takes into account individual immunological and genetic characteristics. In this review, the current knowledge on the epidemiology and genetics of IBD is summarized, and new pathogenetic insights as well as promising future therapeutic options are described.

Have Genomic Discoveries in Inflammatory Bowel Disease Translated into Clinical Progress?

Inflammatory bowel disease (IBD) is a heterogeneous disease that can be challenging to diagnose and manage. As a result, significant efforts have been made in attempting to identify clinical, genomic, and serologic markers of disease that can aid in patient assessment and treatment. Recent genomic discoveries have the potential to change clinical practice by identifying those susceptible to IBD, predict natural history and guide choice of therapy. Panels of genetic and genomic markers are more likely to emerge as clinical tools, as opposed to individual allelic variants. Serology and biomarkers are already being used and guiding management but await integration with genomic panels before achieving their maximal potential. This article reviews the current state of IBD genetics and evolving molecular approaches that may have potential clinical impact.

Digesting the genetics of inflammatory bowel disease: Insights from studies of autophagy risk genes

The success of genetic analyses identifying multiple loci associated with inflammatory bowel disease (IBD) susceptibility has resulted in the identification of several risk genes linked to a common cellular process called autophagy. Autophagy is a process involving the encapsulation of cytosolic cellular components in double-membrane vesicles, their subsequent lysosomal degradation, and recycling of the degraded components for use by the cell. It plays an important part in the innate immune response to a variety of intracellular pathogens, and it is this component of autophagy that appears to be defective in IBD. This has lead to the hypothesis that Crohn's disease may result from an impaired antibacterial response, which leads to ineffective control of bacterial infection, dysbiosis of the intestinal microbiota, and chronic inflammation. Several recurrent themes have surfaced from studies examining the function of autophagy-related genes in the context of IBD, with cellular context, disease status, risk variant effect, and risk gene interplay all affecting the interpretation of these studies. The identification of autophagy as a major risk pathway in IBD is a significant step forward and may lead to pathway-focused therapy in the future; however, there is more to understand in order to unravel the complexity of this disease.

Canine breeds at high risk of developing inflammatory bowel disease in the south-eastern UK

Genetics are an important factor in the development of human inflammatory bowel disease (IBD); however, there is very little information available regarding the role of genetics in canine IBD. The...

Genetics of inflammatory bowel disease in Asia: Systematic review and meta-analysis

Inflammatory bowel diseases (IBD) result from an interaction between genetic and environmental factors. Preliminary findings suggest that susceptibility genes differ between IBD patients in Asia and the West. We aimed to evaluate disease-predisposing genes in Asian IBD patients. A systematic review and meta-analysis were performed of published studies from 1950 to 2010 using keyword searches in MEDLINE, EMBASE, EBM Reviews, and BIOSIS Previews. In all, 477 abstracts were identified and data extracted from 93 studies, comprising 17,976 IBD patients and 27,350 age- and sex-matched controls. Major nucleotide oligomerization domain (NOD)-2 variants in Western Crohn's disease (CD) patients were not associated with CD in Han Chinese, Japanese, South Korean, Indian, and Malaysian populations. New NOD2 mutations were, however, associated with CD in Malaysians (JW1), Han Chinese, and Indians (P268S). Autophagy-related protein 16-linked 1 (ATG16L1) was not associated with CD in East Asians (odds ratio [OR] 0.97; 95% confidence interval [CI] 0.84-1.13). Interleukin (IL)-23R was associated with CD in South Koreans (OR 1.8; 95% CI 1.16-2.82) and a single nucleotide polymorphism in IL-23R (Gly149Arg) was protective of CD in Han Chinese (OR 0.3; 95% CI 0.15-0.60). Tumor necrosis factor (TNF) superfamily gene-15 (SF15) polymorphisms were associated with CD (OR 2.68; 95% CI 1.86-3.86), while TNF-308 polymorphisms (OR 1.82; 95% CI 1.15-2.9), cytotoxic T lymphocyte antigen (CTLA)-4 (OR 2.75; 95% CI 1.22-6.22) and MICA allele (OR 2.41; 95% CI 1.89-3.07) were associated with ulcerative colitis in Asians. Genetic mutations of IBD in Asians differ from Caucasians. New mutations and susceptibility genes identified in Asian IBD patients provide an opportunity to explore new disease-associated mechanisms in this population of rising incidence.

Genetics and pathogenesis of inflammatory bowel disease

Recent advances have provided substantial insight into the maintenance of mucosal immunity and the pathogenesis of inflammatory bowel disease. Cellular programs responsible for intestinal homeostasis use diverse intracellular and intercellular networks to promote immune tolerance, inflammation or epithelial restitution. Complex interfaces integrate local host and microbial signals to activate appropriate effector programs selectively and even drive plasticity between these programs. In addition, genetic studies and mouse models have emphasized the role of genetic predispositions and how they affect interactions with microbial and environmental factors, leading to pro-colitogenic perturbations of the host-commensal relationship.

The Commensal Microbiota and Enteropathogens in the Pathogenesis of Inflammatory Bowel Diseases

Intestinal inflammation arises from abnormal host-microbe interactions. The perturbations of homeostatic coexistence involve host genetic factors, barrier function, innate and adaptive immunity, as well as qualitative and quantitative changes in the composition of the microbiota. Dysbiosis toward selected micro-organisms and decreased complexity of commensal bacteria have been observed in patients with Crohn's disease and ulcerative colitis, but it is not clear whether the dysbiosis contributes to development of inflammatory bowel disease or is instead a consequence of the disease. Pathogens with virulence factors that allow them to breach the intestinal barrier and induce chronic inflammation might mediate the pathogenesis of these diseases. To identify new therapeutic approaches for inflammatory bowel disease, it is important to identify host susceptibility factors involved in the control of microbial infection, characterize potential pathogens, and eliminate them or block the expression of their virulence factors.

Novel development in extraintestinal manifestations and spondylarthropathy

The important co-existence of spondylarthritis (SpA) and inflammatory bowel disease (IBD) within the same individual suggests common etiopathogenic mechanisms. This is supported by intriguing similarities between both diseases at the subclinical and molecular level. The recent advances in IBD genetics have led to the identification of common pathways involved in both IBD and SpA, including bacterial recognition and ER stress. This offers the opportunity to develop potential new therapeutic strategies for both diseases. Transgenic animals which develop both joint and gut inflammation (like the TNF(ΔARE) mice and the HLA-B27 transgenic rats) are a very useful tool to test such novel therapeutics and to get further mechanistic insight into the pathogenetic link between SpA and IBD. This review will focus on the recent scientific progress in our understanding of the link between SpA and IBD. Based on this, potential novel therapeutic strategies are discussed.