scholarly journals Understanding the Molecular Drivers of Disease Heterogeneity in Crohn’s Disease Using Multi-omic Data Integration and Network Analysis

2020 ◽  
Author(s):  
Padhmanand Sudhakar ◽  
Bram Verstockt ◽  
Jonathan Cremer ◽  
Sare Verstockt ◽  
João Sabino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Data Integration ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Treatment Modalities ◽  
Disease Heterogeneity ◽  
Molecular Features ◽  
Genes Encoding

Abstract Crohn’s disease (CD), a form of inflammatory bowel disease (IBD), is characterized by heterogeneity along multiple clinical axes, which in turn impacts disease progression and treatment modalities. Using advanced data integration approaches and systems biology tools, we studied the contribution of CD susceptibility variants and gene expression in distinct peripheral immune cell subsets (CD14+ monocytes and CD4+ T cells) to relevant clinical traits. Our analyses revealed that most clinical traits capturing CD heterogeneity could be associated with CD14+ and CD4+ gene expression rather than disease susceptibility variants. By disentangling the sources of variation, we identified molecular features that could potentially be driving the heterogeneity of various clinical traits of CD patients. Further downstream analyses identified contextual hub proteins such as genes encoding barrier functions, antimicrobial peptides, chemokines, and their receptors, which are either targeted by drugs used in CD or other inflammatory diseases or are relevant to the biological functions implicated in disease pathology. These hubs could be used as cell type–specific targets to treat specific subtypes of CD patients in a more individualized approach based on the underlying biology driving their disease subtypes. Our study highlights the importance of data integration and systems approaches to investigate complex and heterogeneous diseases such as IBD.

scholarly journals Tu1768 – Identifying Molecular Features Contributing to Disease Heterogeneity in Crohn's Disease Using Multi-Omic Data Integration

2019 ◽  
Vol 156 (6) ◽  
pp. S-1117
Author(s):  
Padhmanand Sudhakar ◽  
Bram Verstockt ◽  
Brecht Creyns ◽  
Jonathan Cremer ◽  
Gert A. Van Assche ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Data Integration ◽  
Disease Heterogeneity ◽  
Molecular Features ◽  
Omic Data Integration ◽  
Omic Data

scholarly journals Expression of Cytokine-Coding Genes BMP8B, LEFTY1 and INSL5 Could Distinguish between Ulcerative Colitis and Crohn’s Disease

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1477
Author(s):  
Daša Jevšinek Skok ◽  
Nina Hauptman ◽  
Miha Jerala ◽  
Nina Zidar
Keyword(s):  
Gene Expression ◽  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Experimental Validation ◽  
Expression Profiles ◽  
Statistical Significance ◽  
Gene Expression Profiles ◽  
Cytokine Gene Expression ◽  
Treatment Modalities

Ulcerative colitis (UC) and Crohn’s disease (CD) are characterized by an imbalance between pro-inflammatory and anti-inflammatory cytokines, interfering with the resolution of inflammation. Due to the crucial role of cytokines, new insights into their profiles in UC and CD would help to improve our understanding of pathogenesis and enable the development of new treatment modalities. We provide an expression profile of cytokines in UC and CD, using bioinformatics approach, and experimental validation of expression of the selected genes. We retrieved data and analyzed the cytokine gene expression profiles of UC and CD. From ten genes with inverse expression, common to CD and UC, BMP8B, LEFTY1 and INSL5 were selected for gene expression experimental validation. Experimentally, BMP8B and INSL5 were down-regulated in both CD and UC but followed the bioinformatics trend. The expression of genes LEFTY1 and BMP8B was statistically significant when comparing UC and CD in colon and the expression of gene LEFTY1 showed statistical significance when CD in ileum and colon were compared. Using the bioinformatics approach and experimental validation, we found differences in expression profiles between UC and CD for INSL5, LEFTY1 and BMP8B. These three promising candidate genes need to be further explored at different levels, such as DNA methylation and protein expression, to provide more evidence on their potential diagnostic role in CD and UC.

scholarly journals Diagnostic and Predictive Value of Immune-Related Genes in Crohn’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Bing Yu ◽  
Yi-xin Yin ◽  
Yan-ping Tang ◽  
Kang-lai Wei ◽  
Zhi-gang Pan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Immune Cells ◽  
Predictive Value ◽  
Immune Cell ◽  
Diagnostic Value ◽  
Gene Set Enrichment Analysis ◽  
Ppi Network ◽  
Immune Related Genes

Abnormal immune cell infiltration is associated with the pathogenesis of Crohn’s disease (CD). This study aimed to determine the diagnostic and predictive value of immune-related genes in CD. Seven Gene Expression Omnibus datasets that analyzed the gene expression in CD tissues were downloaded. Single-sample gene set enrichment analysis (ssGSEA) was used to estimate the infiltration of the immune cells in CD tissues. Immune-related genes were screened by overlapping the immune-related genes with differentially expressed genes (DEGs). The protein-protein interaction (PPI) network was used to identify key immune-related DEGs. Diagnostic value of CD and predictive value of anti-TNFα therapy were analyzed. Immunohistochemical (IHC) assay was used to verify gene expression in CD tissues. There were significant differences among CD tissues, paired CD tissues, and normal intestinal tissues regarding the infiltration of immune cells. AQP9, CD27, and HVCN1 were identified as the key genes of the three sub-clusters in the PPI network. AQP9, CD27, and HVCN1 had mild to moderate diagnostic value in CD, and the diagnostic value of AQP9 was better than that of CD27 and HVCN1. AQP9 expression was decreased in CD after patients underwent anti-TNFα therapy, but no obvious changes were observed in non-responders. AQP9 had a moderate predictive value in patients who had undergone treatment. IHC assay confirmed that the expression of AQP9, CD27, and HVCN1 in CD tissues was higher than that in normal intestinal tissues, and AQP9, CD27 was correlated with the activity of CD. Immune-related genes, AQP9, CD27, and HVCN1 may act as auxiliary diagnostic indicators for CD, and AQP9 could serve as a promising predictive indicator in patients who underwent anti-TNF therapy.

TNF-α as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis

2005 ◽  
Vol 109 (2) ◽  
pp. 135-142 ◽  
Author(s):  
Cristina Russo ◽  
Riccardo Polosa
Keyword(s):  
Rheumatoid Arthritis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Allergen Challenge ◽  
Treatment Modalities ◽  
Tnf Α ◽  
Factor Α

TNF-α (tumour necrosis factor-α) is known to play a critical role in the pathogenic mechanisms of a number of chronic inflammatory diseases, including RA (rheumatoid arthritis), Crohn's disease and psoriasis. The notion that TNF-α is released in allergic responses from both mast cells and macrophages via IgE-dependent mechanisms, the demonstration that elevated levels of TNF-α are frequently observed in bronchoalveolar fluid of asthmatic subjects undergoing allergen challenge and the results from exposure studies of TNF-α in vivo showing increases in airway responsiveness in both normal and asthmatic subjects emphasize the importance of TNF-α in the initiation of allergic asthmatic airway inflammation and the generation of airway hyper-responsiveness. Drugs targeting TNF-α have been developed to neutralize the deleterious effects of this inflammatory cytokine and have proved to be safe and effective in the treatment of patients with RA, Crohn's disease and psoriasis refractory to conventional treatments. Biological therapies blocking TNF-α are likely to constitute a considerable advance in the management of those difficult cases of asthma that are particularly resistant to typical treatment modalities. In this review article, we intend to address the potential role of TNF-α in asthma and to put forward the idea that drugs that have been developed to neutralize the deleterious effects of TNF-α may also be useful in the management of chronic severe asthma.

scholarly journals OP15 Multi-omic data integration with network analysis reveals underlying molecular mechanisms driving Crohn’s disease heterogeneity

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S014-S014
Author(s):  
P Sudhakar ◽  
B Verstockt ◽  
J Cremer ◽  
S Verstockt ◽  
T Korcsmaros ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Data Integration ◽  
Molecular Mechanisms ◽  
Local Network ◽  
Perianal Disease ◽  
Network Motifs ◽  
Integration Algorithm ◽  
Disease Heterogeneity ◽  
Clinical Phenotypes

Abstract Background Crohn’s disease (CD) is a heterogeneous disease characterised by clinical phenotypes including differences in disease behaviour, disease location and extraintestinal manifestations. However, the molecular mechanisms which orchestrate CD heterogeneity are relatively unexplored. We tried to infer such mechanisms by integrating two -omic datasets (genomics and blood proteomics) generated from CD patients. Methods 576 unique proteins were measured from blood isolated from CD patients (n = 98) using seven different Olink® panels. All patients were also genotyped using Immunochip. We integrated the above two datasets using an unsupervised data integration algorithm called Multi-Omics Factor Analysis (MOFA). MOFA identifies Latent Factors (LFs) which are hidden representative variables which capture the sources of variation in the provided -omic datasets. LFs capturing less than 2% of the variance were discarded. By using a regression model, we identified explanatory LFs which associate with clinical phenotypes. Proteins and mutations were ranked according to the scores assigned by the corresponding explanatory LF. Potential effects of mutations were inferred by analysing their impacts on coding and non-coding functions. Local network motifs which capture the direct and indirect effects of mutations on protein expression were identified by using the Cytoscape tool ISMAGS. Protein–protein and transcriptional regulatory relationships retrieved from the OmniPath and DoRothEA databases, respectively, were combined to compile the interaction networks used by ISMAGS. Results From the MOFA analysis, we identified five LFs associated with at least one clinical phenotype. Clustering patients along the explanatory LFs achieved meaningful separation of clinical phenotypes such as perianal penetrating disease. The top-ranking proteins associated with perianal-disease included those involved in inflammatory pathways, autophagy or already known to be involved in CD such as IL-8, Rho-GTPase activators, MIF, Caspase 8, TRIM5 and SNAP29. The networks corresponding to the top ranking proteins associated with the perianal phenotype could be broken down into 102 local network motifs. These local motifs pointed out control mechanisms by which a total of 7 mutations mapped to transcription factors (SMAD3, BACH2) and post-translational regulators (such as IFNGR2, IL10, IL2RA, SLC2A4RG and ZMIZ1) could potentially regulate perianal disease‘s pathophysiology and could, therefore, be considered novel drug targets. Conclusion By using integrated signature profiles generated from multiple -omic datasets, we identified molecular mechanisms which could potentially describe CD phenotypes such as the occurrence of perianal disease.

scholarly journals New IBD Markers: Definition of Disease Heterogeneity

1995 ◽  
Vol 9 (6) ◽  
pp. 301-304
Author(s):  
Stephan R Targan
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Serum Markers ◽  
Treatment Modalities ◽  
Mucosal Inflammation ◽  
Disease Heterogeneity ◽  
Clinical Phenotypes ◽  
Tnf Α ◽  
Different Types

There is emerging evidence that serum and mucosal markers differentiate Crohn's disease from ulcerative colitis; moreover, subgroups can be defined within each disease. Subgroups have been defined on the basis of genetic, serum and mucosal markers, and are associated with different clinical phenotypes. Antineutrophil cytoplasmic antibodies (ANCA) define subgroups of patients with both ulcerative colitis and Crohn's disease. A new serum marker, 20P-1, has been found in 60 to 70% of patients with Crohn's disease, 20% of ulcerative colitis patients and approximately 10% of the normal control population. The 20P-1 marker further stratifies the subgroups of patients defined by ANCA. In addition to serum markers, genes regulating production of the cytokine tumour necrosis factor (TNF)-α have been shown to be different across ulcerative colitis and Crohn's disease, and within the ulcerative colitis group. Serum markers may reflect differential mucosal inflammatory responses as is best shown by ANCA. B cell clones within the mucosa of 60 to 70% of patients with ulcerative colitis produce ANCA spontaneously. Studies currently underway demonstrate different TNF- α production within the mucosa of patients with Crohn's disease compared with ulcerative colitis patients. Correlation studies with TNF-α microsatellites (genes) are being performed. These markers are the focus of a trial using molecularly engineered products that are capable of inhibiting TNF-α to identify patients likely to respond to anti-TNF therapy. In this constantly evolving climate of understanding and treating inflammatory bowel disease, serum, mucosal and genetic markers as well as genetic associations are being formed to determine clinical phenotypes that may be differentially responsive to very selected treatment modalities. These advances highlight the likelihood that the various markers define different types of mucosal inflammation. The different types of mucosal inflammation will determine the response or resistance to certain types of therapeutic options.

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
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