Abstract
Inflammatory bowel disease (IBD) manifests as a complex disease resulting from gene–environment interactions or as a monogenic disease resulting from deleterious mutations. While monogenic IBD is predominantly pediatric, only one-quarter of complex IBD is pediatric. In this study, we were the first to systematically compare genetic architecture between monogenic and complex pediatric and adult IBD on genetic and molecular pathway levels. Genes reported as causal for monogenic pediatric IBD and related syndromes and as risk factors for pediatric and adult complex IBD were analyzed using CytoScape and ClueGO software tools to elucidate significantly enriched Gene Ontology (GO) terms. Despite the small overlap (seven genes) between monogenic IBD genes (85) and complex IBD loci (240), GO analysis revealed several enriched GO terms shared between subgroups (13.9%). Terms Th17 cell differentiation and Jak/STAT signaling were enriched in both monogenic and complex IBD subgroups. However, primary immunodeficiency and B-cell receptor signaling pathway were specifically enriched only for pediatric subgroups, confirming existing clinical observations and experimental evidence of primary immunodeficiency in pediatric IBD patients. In addition, comparative analysis identified patients below 6 years of age to significantly differ from complex pediatric and adult IBD and could be considered a separate entity.
Highlights
Inflammatory bowel disease (IBD) is an immune-mediated disease of the gastrointestinal tract
Pediatric IBD is more commonly classified as Crohn’s disease (CD) than ulcerative colitis (UC); a significant fraction is classified as indeterminate colitis [5,14]
Studies describing pediatric IBD and IBD-like syndromes and associated genes were included on the basis of the following criteria: disorder is described or presented itself as inflammatory bowel disease, Crohn’s disease, ulcerative colitis or indeterminate colitis; disorder first affects patients younger than 18 years; disorder has an accurately described disease onset; disorder is monogenic or shown to be highly penetrant (>90%); disorder is causally linked to a known genetic locus
Summary
Inflammatory bowel disease (IBD) is an immune-mediated disease of the gastrointestinal tract. Whole-exome sequencing followed by replication GWAS revealed an overlap of genetic loci associated with pediatric and adult onset IBD in Poland, as well as a significant accumulation of rare and deleterious variants in affected children [27]. GWASs had success in identifying loci with enhanced contribution in pediatric-onset UC [29] This suggests that the pathogenesis of pediatric and adult inflammatory bowel disease does not differ much. No study has performed GO analysis of genes causative for pediatric IBD and IBD-like disorders or compared them to complex pediatric and adult IBD. Knowledge of the genetic landscape that shapes pediatric-onset IBD would allow for gene panel optimization to reduce cost of genetic testing and increase its availability To this end, we gathered genes with variants causative for pediatric IBD and IBD-like disorders to elucidate enriched biological processes using GO analysis
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