scholarly journals Network Analysis of Inflammatory Bowel Disease Reveals PTPN2 As New Monogenic Cause of Intestinal Inflammation

2019 ◽  
Author(s):  
Marianna Parlato ◽  
Julia Pazmandi ◽  
Qing Nian ◽  
Fabienne Charbit-Henrion ◽  
Bernadette Bègue ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Random Walk ◽  
Bowel Disease ◽  
Fine Tuning ◽  
Molecular Networks ◽  
Genome Wide Association Studies ◽  
Causal Genes ◽  
Disease Module ◽  
Inflammatory Bowel ◽  
Stat Pathway

ABSTRACTBACKGROUND & AIMSGenome-wide association studies (GWAS) have uncovered multiple loci associated with inflammatory bowel disease (IBD), yet delineating functional consequences is complex. We used a network-based approach to uncover traits common to monogenic and polygenic forms of IBD in order to reconstruct disease relevant pathways and prioritize causal genes.METHODSWe have used an iterative random walk with restart to explore network neighborhood around the core monogenic IBD cluster and disease-module cohesion to identify functionally relevant GWAS genes. Whole exome sequencing was used to screen a cohort of monogenic IBD for germline mutations in top GWAS genes. One mutation was identified and validated by a combination of biochemical approaches.RESULTSMonogenic IBD genes clustered siginificantly on the molecular networks and had central roles in network topology. Iterative random walk from these genes allowed to rank the GWAS genes, among which 14 had high disease-module cohesion and were selected as putative causal genes. As a proof of concept, a germline loss of function mutation was identified in PTPN2, one of the top candidates, as a novel genetic etiology of early-onset intestinal autoimmunity. The mutation abolished the catalytic activity of the enzyme, resulting in haploinsufficiency and hyper-activation of the JAK/STAT pathway in lymphocytes.CONCLUSIONSOur network-based approach bridges the gap between large-scale network medicine prediction and single-gene defects and underscores the crucial need of fine tuning the JAK/STAT pathway to preserve intestinal immune homeostasis. Our data provide genetic-based rationale for using drugs targeting the JAK/STAT pathway in IBD.

Very early onset inflammatory bowel disease (VEO-IBD); spectrum of clinical presentation, diagnostic tools and outcome in children

2021 ◽  
Vol 71 (10) ◽  
pp. 2350-2354
Author(s):  
Huma Arshad Cheema ◽  
Nadia Waheed ◽  
Anjum Saeed ◽  
Zafar Fayyaz ◽  
Muhammad Nadeem Anjum ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Early Onset ◽  
Clinical Presentation ◽  
Association Studies ◽  
Diagnostic Tools ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Basic Work ◽  
Inflammatory Bowel

Background: Very early-onset inflammatory bowel disease (VEO-IBD) is defined as diagnosis of Ulcerative Colitis (UC) or Crohn’s Disease (CD) in children under six years of age. Genome wide association studies have linked a strong genetic component responsible for VEO-IBD. Approximately, 30-40% children of VEO-IBD have underlying immunodeficiency states. We aimed to study the spectrum of presentation, underlying monogenetic defects and outcome in VEO-IBD. Methods: This is a prospective, observational study conducted at division of Gastroenterology, the Children's Hospital & the Institute of Child Health, Lahore, over 2 years. Children developing features of IBD under six-years of age were included. Data included demography, clinical presentation, diagnostic tools and outcome. Gastroscopy and colonoscopy were performed in all patients in addition to basic work up done for associatedimmunodeficiency states and molecular genetics.  SPSS version 21 was used for analysis. Continuous...

scholarly journals Application of Proteomics to Inflammatory Bowel Disease Research: Current Status and Future Perspectives

2019 ◽  
Vol 2019 ◽  
pp. 1-24 ◽  
Author(s):  
Arash Assadsangabi ◽  
Caroline A. Evans ◽  
Bernard M. Corfe ◽  
Alan Lobo
Keyword(s):  
Inflammatory Bowel Disease ◽  
Cancer Progression ◽  
Bowel Disease ◽  
Biomarker Discovery ◽  
Association Studies ◽  
Disease Process ◽  
Current Status ◽  
Genome Wide Association Studies ◽  
Susceptibility Loci ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) is a chronic relapsing/remitting inflammatory illness of the gastrointestinal tract of unknown aetiology. Despite recent advances in decoding the pathophysiology of IBD, many questions regarding disease pathogenesis remain. Genome-wide association studies (GWAS) and knockout mouse models have significantly advanced our understanding of genetic susceptibility loci and inflammatory pathways involved in IBD pathogenesis. Despite their important contribution to a better delineation of the disease process in IBD, these genetic findings have had little clinical impact to date. This is because the presence of a given gene mutation does not automatically correspond to changes in its expression or final metabolic or structural effect(s). Furthermore, the existence of these gene susceptibility loci in the normal population suggests other driving prerequisites for the disease manifestation. Proteins can be considered the main functional units as almost all intracellular physiological functions as well as intercellular interactions are dependent on them. Proteomics provides methods for the large-scale study of the proteins encoded by the genome of an organism or a cell, to directly investigate the proteins and pathways involved. Understanding the proteome composition and alterations yields insights into IBD pathogenesis as well as identifying potential biomarkers of disease activity, mucosal healing, and cancer progression. This review describes the state of the art in the field with respect to the study of IBD and the potential for translation from biomarker discovery to clinical application.

JAK–STAT pathway targeting for the treatment of inflammatory bowel disease

2020 ◽  
Vol 17 (6) ◽  
pp. 323-337 ◽  
Author(s):  
Azucena Salas ◽  
Cristian Hernandez-Rocha ◽  
Marjolijn Duijvestein ◽  
William Faubion ◽  
Dermot McGovern ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Inflammatory Bowel ◽  
Stat Pathway

scholarly journals The Effect of a Fennel Extract on the STAT Signaling and Intestinal Barrier Function

2021 ◽  
Author(s):  
John Rabalais ◽  
Philip Kozan ◽  
Tina Lu ◽  
Nassim Durali ◽  
Kevin Okamoto ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Protective Effect ◽  
Bowel Disease ◽  
Barrier Function ◽  
Intestinal Barrier Function ◽  
Protective Effects ◽  
Foeniculum Vulgare ◽  
Inflammatory Bowel ◽  
Stat Pathway

Background: Foeniculum vulgare, F. vulgare, commonly known as fennel, is believed to be one of the worlds oldest medicinal herbs and has been exploited by people for centuries as a nutritional aid for digestive disorders. In many southeast Asian countries it is ingested as an after-meal snack, mukhvas, due to its breath-freshening and digestive aid properties. F. vulgare is used in some countries, such as Iran, as a complementary and alternative treatment for inflammatory bowel disease (IBD). Methods: This study investigated the effects of F. vulgare on the barrier function of the intestinal epithelium Signal Transducer and Activator of Transcription (STAT) pathway, which is active in inflammatory bowel disease. To study the protective effects of F. vulgare extract in vitro, monolayers derived from the T84 colonic cell line were challenged with interferon-gamma (IFN-γ) and monitored with and without F. vulgare extract. To complement our in vitro studies, the dextran sodium sulfate induced murine colitis model was employed to ascertain whether the protective effect of F. vulgare extract can be recapitulated in vivo. Results: F. vulgare extract was shown to exert a protective effect on TEER in both T84 and murine models and showed increases in tight junction-associated mRNA in T84 cell monolayers. Both models demonstrated significant decreases in phosphorylated STAT1 (pSTAT1), indicating reduced activation of the STAT pathway. Additionally, mice treated with F. vulgare showed significantly lower ulcer indices than control mice. Conclusions: We conclude barrier function of the gastrointestinal tract is improved by F. vulgare, suggesting the potential utility of this agent as an alternative or adjunctive therapy in IBD.

scholarly journals Identifying novel high-impact rare disease-causing mutations, genes and pathways in exomes of Ashkenazi Jewish inflammatory bowel disease patients

2020 ◽  
Author(s):  
Yiming Wu ◽  
Kyle Gettler ◽  
Mamta Giri ◽  
Dalin Li ◽  
Cigdem Sevim Bayrak ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Association Studies ◽  
High Impact ◽  
Genomic Research ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Common Genetic Variants ◽  
Inflammatory Bowel ◽  
Shared Risk

ABSTRACTInflammatory bowel disease (IBD) is a group of chronic diseases, affecting different parts of the gastrointestinal tract, that mainly comprises Crohn’s Disease (CD) and Ulcerative Colitis (UC). Most IBD genomic research to date has involved genome-wide association studies (GWAS) of common genetic variants, mostly in Europeans, resulting in the identification of over 200 risk loci. The incidence of IBD in Ashkenazi Jews (AJ) is particularly high compared to other population groups and rare protein-coding variants are significantly enriched in AJ. These variants are expected to have a larger phenotypic effect and are hypothesized to complement the missing heritability that cannot be fully addressed by GWAS in IBD. Therefore, we genetically identified 4,974 AJs IBD cases and controls from whole exome sequencing (WES) data from the NIDDK IBD Genetics Consortium (IBDGC). We selected credible rare variants with high predicted impact, aggregated them into genes, and performed gene burden and pathway enrichment analyses to identify 7 novel plausible IBD-causing genes:NCF1, CES1, ICAM1, INPP5D, ABCB1, IL33 and TLR4. We further perform bulk and single-cell RNA sequencing, demonstrating the likely relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of AJ adult IBD displays a significant overlap with very early onset IBD (VEOIBD) genetics. At the variant level, we performed Phenome-wide association studies (PheWAS) in the UK Biobank to replicate risk sites in IBD and reveal shared risk sites with other diseases. Finally, we showed that a polygenic risk score (PRS) has high power to differentiate AJ IBD cases from controls when using rare and high impact variants.

scholarly journals Causal Linkage Between Inflammatory Bowel Disease and Primary Sclerosing Cholangitis: A Two-Sample Mendelian Randomization Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Ying Xie ◽  
Xuejie Chen ◽  
Minzi Deng ◽  
Yuhao Sun ◽  
Xiaoyan Wang ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Primary Sclerosing Cholangitis ◽  
Bowel Disease ◽  
Sclerosing Cholangitis ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Causal Association ◽  
Statistical Heterogeneity ◽  
Inflammatory Bowel

BackgroundObservational studies suggest an association between inflammatory bowel disease (IBD) [including ulcerative colitis (UC) and Crohn’s disease (CD)] and Primary sclerosing cholangitis (PSC), but the causal association between the two diseases remains unclear.MethodsWe used two-sample Mendelian randomization (MR) to estimate the causal association between IBD and PSC. We chose single nucleotide polymorphisms (SNPs) data for analysis, obtained from previous genome-wide association studies (GWASs). Pleiotropy, heterogeneity, and sensitivity analyses were performed for quality control.ResultsWe found that the causal associations between IBD (both UC and CD) and PSC were significant (e.g., IBD and PSC, Robust adjusted profile score (RAPS) OR = 1.29, 95% CI 1.16∼1.44, p< 0.01; UC and PSC, RAPS OR = 1.40, 95% CI 1.23∼1.58, p< 0.01; CD and PSC, RAPS OR = 1.13, 95% CI 1.02∼1.26, p = 0.02). MR Egger, IVW, and ML tests found statistical heterogeneity between determined IV estimates. The leave-one-out analysis also indicated the sensitivity of the SNPs (e.g., IBD and PSC, MR-Egger Q = 644.30, p< 0.01; UC and PSC, MR-Egger Q = 378.30, p< 0.01; UC and PSC, MR-Egger Q = 538.50, p < 0.01).ConclusionMR analyses support the positive causal effect of IBD (including UC and CD) on PSC in a European population. We provide suggestions for preventing and treating the two diseases.

scholarly journals Lymphocyte Antigen 75 Polymorphisms Are Associated with Disease Susceptibility and Phenotype in Japanese Patients with Inflammatory Bowel Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Atsuhiro Hirayama ◽  
Satoru Joshita ◽  
Kei Kitahara ◽  
Kenji Mukawa ◽  
Tomoaki Suga ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Association Studies ◽  
Japanese Patients ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Lymphocyte Antigen ◽  
Genome Wide ◽  
Surgical History ◽  
Inflammatory Bowel

Recent genome-wide association studies have rapidly improved our understanding of the molecular pathways leading to inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC). Although several reports have demonstrated that gene single nucleotide polymorphisms (SNPs) are associated with susceptibility to IBD, its precise genetic factors have not been fully clarified. Here, we performed an association analysis between lymphocyte antigen 75 (LY75) genetic variations and IBD susceptibility or phenotype. SNPs were genotyped in 51 CD patients, 94 UC patients, and 269 healthy controls of Japanese ethnicity. We detected a significant relationship with CD susceptibility for the rs16822581 LY75 SNP (P=0.045). One haplotype (GT, P=0.042) was also associated with CD susceptibility, while another carrying the opposite SNP (CA) was linked to an absence of surgical history for CD. Our findings confirm that LY75 is involved in CD susceptibility and may play a role in disease activity in the Japanese population.

scholarly journals Molecular Profiling of Inflammatory Bowel Disease: Is It Ready for Use in Clinical Decision-Making?

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 535 ◽  
Author(s):  
Ho-Su Lee ◽  
Isabelle Cleynen
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Clinical Decision Making ◽  
Association Studies ◽  
Disease Onset ◽  
Molecular Profiling ◽  
Response To Therapy ◽  
Current Status ◽  
Genome Wide Association Studies ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) is a heterogeneous disorder in terms of age at onset, clinical phenotypes, severity, disease course, and response to therapy. This underlines the need for predictive and precision medicine that can optimize diagnosis and disease management, provide more cost-effective strategies, and minimize the risk of adverse events. Ideally, we can leverage molecular profiling to predict the risk to develop IBD and disease progression. Despite substantial successes of genome-wide association studies in the identification of genetic variants affecting IBD susceptibility, molecular profiling of disease onset and progression as well as of treatment responses has lagged behind. Still, thanks to technological advances and good study designs, predicting phenotypes using genomics and transcriptomics in IBD has been rapidly evolving. In this review, we summarize the current status of prediction of disease risk, clinical course, and response to therapy based on clinical case presentations. We also discuss the potential and limitations of the currently used approaches.

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