scholarly journals P076 A gene expression outlier strategy towards identifying molecular causes of Crohn's disease

2012 ◽  
Vol 6 ◽  
pp. S41
Author(s):  
G.W. Sewell ◽  
P.J. Smith ◽  
A.P. Levine ◽  
C.M. McDonald ◽  
S.L. Bloom ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease

scholarly journals ZBTB6 is hyper-methylated and differentially expressed in the blood of patients with Crohn’s disease.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
The United States ◽  
Differentially Expressed ◽  
Economic Productivity ◽  
Unbiased Manner ◽  
Inflammatory Bowel ◽  
Disease Analysis ◽  
Broad Complex

Crohn’s disease, an inflammatory bowel disease of the gastrointestinal tract (1), causes significant morbidity and nearly 3.5 billion dollars in lost economic productivity in the United States (2) due to complications of the disease. We mined transcriptome and methylome datasets (3, 4) to understand, in an unbiased manner, the most significant changes in gene expression and DNA methylation in the hematopoietic system of patients with Crohn’s disease (CD). We identified the zinc finger and BTB (broad complex, tramtrack, bric-à-brac) domain-containing gene ZBTB6 (5, 6) as one of the most differentially expressed genes in the whole blood of patients with Crohn’s disease. Analysis of a separate data revealed that the ZBTB6 locus was one of the most differentially methylated sites globally in the blood of patients with Crohn’s disease when compared to the blood of healthy patients. ZBTB6 is differentially methylated and differentially expressed in the blood of patients with Crohn’s disease, and more significantly so than the vast majority of the human genome. These data point to inhibition of ZBTB6 gene expression by hyper-methylation of the ZBTB6 locus and suggest that titration of some function or transcriptional target of ZBTB6 may be an important event in the pathogenesis of Crohn’s disease.

IDENTIFYING RELEVANT PATHWAYS AND BIOMARKERS IN CROHN’S DISEASE USING CONTEXTUALIZED METABOLIC NETWORK MODEL

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S9-S10
Author(s):  
Brooklyn McGrew ◽  
Aman Shrivastava ◽  
Philip Fernandes ◽  
Lubaina Ehsan ◽  
Yash Sharma ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Fatty Acid ◽  
Crohn's Disease ◽  
Fatty Acid Synthesis ◽  
Metabolic Pathway ◽  
Metabolic Pathways ◽  
Acid Synthesis ◽  
Transcriptomic Data ◽  
Context Specific

Abstract Background Candidate markers for Crohn’s Disease (CD) may be identified via gene expression-based construction of metabolic networks (MN). These can computationally describe gene-protein-reaction associations for entire tissues and also predict the flux of reactions (rate of turnover of specific molecules via a metabolic pathway). Recon3D is the most comprehensive human MN to date. We used publicly available CD transcriptomic data along with Recon3D to identify metabolites as potential diagnostic and prognostic biomarkers. Methods Terminal ileal gene expression profiles (36,372 genes; 218 CD. 42 controls) from the RISK cohort (Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn’s Disease) and their transcriptomic abundances were used. Recon3D was pruned to only include RISK dataset transcripts which determined metabolic reaction linkage with transcriptionally active genes. Flux balance analysis (FBA) was then run using RiPTiDe with context specific transcriptomic data to further constrain genes (Figure 1). RiPTiDe was independently run on transcriptomic data from both CD and controls. From the pruned and constricted MN obtained, reactions were extracted for further analysis. Results After applying the necessary constraints to modify Recon3D, 527 CD and 537 control reactions were obtained. Reaction comparison with a publicly available list of healthy small intestinal epithelial reactions (n=1282) showed an overlap of 80 CD and 84 control reactions. These were then further grouped based on their metabolic pathways. RiPTiDe identified context specific metabolic pathway activity without supervision and the percentage of forward, backward, and balanced reactions for each metabolic pathway (Figure 2). The metabolite concentrations in the small intestine was altered among CD patients. Notably, the citric acid cycle and malate-aspartate shuttle were affected, highlighting changes in mitochondrial metabolic pathways. This is illustrated by changes in the number of reactions at equilibrium between CD and control. Conclusions The results are relevant as cytosolic acetyl-CoA is needed for fatty acid synthesis and is obtained by removing citrate from the citric acid cycle. An intermediate removal from the cycle has significant cataplerotic effects. The malate-aspartate shuttle also allows electrons to move across the impermeable membrane in the mitochondria (fatty acid synthesis location). These findings are reported by previously published studies where gene expression for fatty acid synthesis is altered in CD patients along with mitochondrial metabolic pathway changes, resulting in altered cell homeostasis. In-depth analysis is currently underway with our work supporting the utility of potential metabolic biomarkers for CD diagnosis, management and improved care.

scholarly journals P014 Identification of Crohn’s disease immunopathotypes

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S137-S137
Author(s):  
H M Baer ◽  
E MacDonald ◽  
A Ferguson ◽  
A M Scott ◽  
M I Khan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Immune Responses ◽  
Mononuclear Cells ◽  
Local Immune Response ◽  
Cross Sectional ◽  
Treatment Responses ◽  
Colonic Biopsies

Abstract Background Crohn’s disease (CD) is a chronic inflammatory gastrointestinal condition, with globally increasing incidence. Patients with CD suffer from a loss of tolerance towards their commensal microbiota causing an aberrant immune response, occurring in a protracted relapse and remission cycle. Although a variety of frontline therapies is currently available, including targeted therapies such as biologic drugs, 30–40% of CD patients still require surgery to manage the disease. At present, the immunobiology of CD is not fully understood. However, differences in immune responses between patients might play an important role in diverse treatment responses. The aim of this study was to identify differences in peripheral and local immune responses of CD to understand differences in disease behaviour and treatment outcome. Methods Peripheral blood mononuclear cells and plasma were isolated from whole blood of a cross-sectional CD patient cohort (nCD = 12) and normal controls (NC, nNC = 28). Flow cytometry analysis and multiplex assays were used to quantify immune cell populations and cytokine levels, respectively. The local immune response was analysed by bulk RNA sequencing of mucosal colonic biopsies either from inflamed CD or normal tissue. Gene signatures were then followed up by validation in publicly deposited gene expression datasets (nCD = 36, nNC = 24), and by measurement of specific proteins using our archived samples. Results Peripheral immunophenotyping of the initial cross-sectional study displayed three different types of CD patients, characterised by either a decrease in leukocyte populations, an increase of cytokines, or a change in both. Analysis of the RNAseq data derived from colonic biopsies revealed four distinct clusters in genes associated with the immune response in CD patients. Further pathway analysis showed one cluster with an enriched B cell signature and another cluster with an elevated macrophage and neutrophil response. We utilised publicly available gene expression datasets to validate these signatures in a larger cohort and identified a selection of patients with an up-regulated pro-inflammatory macrophage response. Using correlation analysis, we suggest an immunopathotype with increased macrophage activation which is potentially associated with a more severe form of the disease. Conclusion We have identified distinct immunopathotypes in both the peripheral and local immune response of CD patients. Further investigation will correlate these distinct immune responses in CD with clinical parameters, to understand associations between diverse treatment responses and disease behaviours.

scholarly journals Peripheral Blood Based Discrimination of Ulcerative Colitis and Crohn’s Disease from Non-IBD Colitis by Genome-Wide Gene Expression Profiling

2011 ◽  
Vol 30 (1) ◽  
pp. 1-17 ◽  
Author(s):  
Ferenc Sipos ◽  
Orsolya Galamb ◽  
Barnabás Wichmann ◽  
Tibor Krenács ◽  
Kinga Tóth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Peripheral Blood ◽  
Independent Set ◽  
Molecular Diagnostic ◽  
Blood Samples ◽  
Specificity And Sensitivity

A molecular diagnostic assay using easily accessible peripheral blood would greatly assist in the screening and diagnosis of ulcerative colitis (UC) and Crohn’s disease (CD). Transcriptional profiles in blood/biopsy samples from 12 UC (6/12), 9 CD (5/9), 6 non-inflammatory bowel disease (non-IBD) colitis (6/0), and 11 healthy (11/11) patients were assessed by Affymetrix HGU133Plus2.0 microarrays. Prediction analysis of microarrays, discriminant and ROC analyses were performed, the results were validated by RT-PCR and immunohistochemistry using also an independent set of samples (15 blood samples, 45 biopsies). A set of 13 transcripts was differentially expressed in IBD, non-IBD controls and healthy blood samples (100% specificity and sensitivity). Validated difference was found in 16 transcripts between UC, non-IBD and normal blood, and 4 transcripts between CD, non-IBD and normal samples. UC and CD blood cases could be also distinguished by 5 genes with 100% specificity and sensitivity. Some disease associated alterations in blood transcripts were also detected in colonic tissue. IBD subtypes may be discriminated from non-IBD (diverticulitis, infective and ischemic colitis)in vitrofrom peripheral blood by screening for differential gene expression revealed in this study. Transcriptional profile alterations in peripheral blood can be located in diseased colon.

Tu1932 Mucosal Gene Expression Differences Between Early and Post-Operative Recurrent/Late Ileal Crohn's Disease Suggest Increased Inflammatory Load in Early Disease

2012 ◽  
Vol 142 (5) ◽  
pp. S-881 ◽  
Author(s):  
Ingrid Arijs ◽  
Jan Van der Goten ◽  
Gert De Hertogh ◽  
Marc Ferrante ◽  
Kathleen Machiels ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Early Disease

scholarly journals The Crohn’s disease associated SNP rs6651252 impacts MYC gene expression in human colonic epithelial cells

PLoS ONE ◽  
2019 ◽  
Vol 14 (2) ◽  
pp. e0212850 ◽  
Author(s):  
Stephen M. Matthews ◽  
Melanie A. Eshelman ◽  
Arthur S. Berg ◽  
Walter A. Koltun ◽  
Gregory S. Yochum
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Epithelial Cells ◽  
Colonic Epithelial Cells ◽  
Myc Gene

scholarly journals P061 The molecular landscape of perianal fistula in Crohn’s disease: opportunities for new therapeutic approaches

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S165-S165
Author(s):  
G Bislenghi ◽  
B Verstockt ◽  
J Sabino ◽  
C Caenepeel ◽  
S Verstockt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Differential Gene Expression ◽  
Perianal Fistula ◽  
Rectal Mucosa ◽  
Fistula Tract ◽  
Potential Contribution ◽  
Differential Gene ◽  
Molecular Landscape

Abstract Background Perianal Crohn’s disease (CD) is a debilitating condition, often refractory to medical therapy and requiring repetitive surgical interventions. Nonetheless, its pathophysiology is very poorly understood. Hence, we molecularly characterised the fistula tract and compared it to the molecular landscape of its inner rectal orifice. Methods We collected paired surgical biopsies from the fistula tract and the inner rectal fistula orifice in 29 CD patients with draining perianal fistula, requiring surgical examination under anaesthesia. RNA was extracted and single-end RNA sequencing performed using Illumina HiSeq4000. Sequencing data were analysed through differential gene expression (DESeq2) and corrected for the presence of proctitis. A false discovery rate of 0.001 was considered significant. In addition, cellular deconvolution methods (CIBERSORT) were applied to study the cellular composition of the fistula tract. Results Differential gene expression revealed 2701 transcripts being differentially expressed (1727 up, 974 down in fistula) between the fistula tract and the paired rectal mucosa. The top upregulated gene, LBP (fold change [FC]=2858.8, p = 3.6E−13), highlights the potential contribution of the microbiome. LBP has a central role in the innate immune system by binding to bacterial lipopolysaccharides (LPS) and facilitating the affinity between LPS and CD14, with the subsequent release of various cytokines. Several extracellular matrix proteins could be identified within the top 25 of upregulated genes, including MMP13 (FC = 358.8, p = 1.3E−11), ADAM12 (FC = 175.6, p = 1.4E−12), COL1A1 (FC = 77.1, p = 2.7E−10) and COL5A3 (FC = 32.1, p = 1.7E−12), emphasising the intense tissue remodelling going on in the fistula tract. Despite correcting for the confounding effect of proctitis, the fistula tract expressed higher levels of IL6 (FC = 133.1, p = 3.7E−9), TNF(FC = 14.2, p = 4.8E−5), OSM (FC = 24.3, p = 8.9E−5), IL12p40 (FC = 10.0, p = 8.1E−3), integrin α 4 (FC = 4.5, p = 9.3E−3), integrin β 7(FC = 3.8, p = 4.1E−3) but not IL23p19 (FC = 1.2, p = 0.9). Top downregulated genes were linked to the intestinal epithelium, including KRT19 (FC = −489.1, p = 5.5E−17), KRT8 (FC = −324.0, p = 1.1E−16), CEACAM6 (FC=−515.1, p = 4.5E−16) and MUC2 (FC=−795.4, p = 3.0E−15). Cellular deconvolution identified CD4 memory resting T cells (18.5%), M0 macrophages (17%), M2 macrophages (15.2%), neutrophils (9.2%) and plasma cells (7.5%) as the most abundant cells within the fistula tract. Conclusion We molecularly characterised the fistula tract in perianal CD and identified clear biological differences in comparison to the luminal tract, highlighting the potential of new therapeutic targets and cell types driving this debilitating condition.

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