Project description:Background & Aims: Most inflammatory bowel diseases (IBDs) are classic polygenic disorders represented by common alleles. However, multiple determinants of very early-onset IBD characterized by a more extensive disease course remain largely unknown. The present study aimed to define the genetic architecture of pediatric and adult-onset IBDs in the Polish population. Results: Of 82 SNPs validated/replicated for association with IBD, a novel BRD2 (rs1049526) association was found in both pediatric (OR= 2.35) and adult (OR= 2.66) patients. Thirty SNPs were shared between pediatric and adult patients; 22 and 30 were unique to adult-onset and pediatric-onset IBD, respectively. WES identified numerous rare/infrequent, potentially deleterious variants in IBD-associated or innate immunity-associated genes. Both groups of variants were over-represented in affected children. Two highly deleterious homozygous variants, HLA-DRB1 c.565_566insC and NCF4 p.Arg8Trp, were found in two affected children, and WAS p.Glu131Lys was found in one child and one adult patient. Conclusions: Our GWAS revealed differences in the polygenic architecture of pediatric- and adult-onset IBD. A significant accumulation of rare/low frequency deleterious variants in affected children suggests a contribution by yet unexplained genetic components.
Project description:Expression profiling of human colon mucosa samples aquired from inflammatory bowel disease patients and healthy controls. Expression profiling was done using Illumina Human HT-12 arrays, and data analysis was performed using tools from the Bioconductor package
Project description:Dysregulated proteolysis plays a pivotal role in the pathophysiology of inflammatory bowel disease. Nonetheless, the identity of overactive proteases released by human colonic mucosa remains unknown. Herein, we employed a serine protease-targeted activity-based probe (ABP) coupled with mass spectral analysis to identify active forms of proteases secreted by the colonic mucosa of healthy volunteers and inflammatory bowel disease patients. With this approach, we identified seven active serine proteases: cathepsin G, plasma kallikrein, plasmin, tryptase, chymotrypsin-like elastase 3A, aminopeptidase B, and thrombin. Furthermore, cathepsin G and thrombin were overactive in supernatants from inflammatory bowel disease patients once compared to healthy volunteers.
Project description:Abstract: Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/ precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway.
Project description:Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is associated with a loss or an imbalance of host-microbe interactions. Depletion-assisted deep metaproteomics was employed to reveal disease-specific networks of host-microbial protein associations in IBD.
Project description:The series was designed to identify new genes involved in the pathophysiology of inflammatory bowel disease (Crohn's disease and ulcerative colitis). This series represents a group of 31 samples, subdivided into 3 groups: 1) Normal controls: 11 samples; 2) patients with Crohn's diseases: 10 samples; 3) patients with ulcerative colitis: 10 samples. Each sample originated from a different patient or normal control, in total n=31 individuals were examined. Keywords = Inflammatory bowel disease Keywords = Crohn's disease Keywords = ulcerative colitis Keywords = expression screening Keywords = expression profiling Keywords: other