{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T08:32:58Z","timestamp":1775205178819,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T00:00:00Z","timestamp":1606348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004329","name":"Javna Agencija za Raziskovalno Dejavnost RS","doi-asserted-by":"publisher","award":["P3\u20130067"],"award-info":[{"award-number":["P3\u20130067"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004329","name":"Javna Agencija za Raziskovalno Dejavnost RS","doi-asserted-by":"publisher","award":["J3-9258"],"award-info":[{"award-number":["J3-9258"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Inflammatory bowel disease (IBD) manifests as a complex disease resulting from gene\u2013environment 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.<\/jats:p>","DOI":"10.3390\/jpm10040243","type":"journal-article","created":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T09:04:15Z","timestamp":1606381455000},"page":"243","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Molecular Genetic Architecture of Monogenic Pediatric IBD Differs from Complex Pediatric and Adult IBD"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1110-5345","authenticated-orcid":false,"given":"Gregor","family":"Jezernik","sequence":"first","affiliation":[{"name":"Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Du\u0161anka","family":"Mi\u010deti\u0107-Turk","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1624-9428","authenticated-orcid":false,"given":"Uro\u0161","family":"Poto\u010dnik","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia"},{"name":"Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova Ulica 17, 2000 Maribor, Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1097\/MIB.0b013e318280b13e","article-title":"Incidence, clinical characteristics, and natural history of pediatric IBD in Wisconsin: A population-based epidemiological study","volume":"19","author":"Adamiak","year":"2013","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"j2083","DOI":"10.1136\/bmj.j2083","article-title":"Diagnosis and management of inflammatory bowel disease in children","volume":"357","author":"Oliveira","year":"2017","journal-title":"BMJ"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"921730","DOI":"10.1155\/2015\/921730","article-title":"Incidence Trends and Geographical Variability of Pediatric Inflammatory Bowel Disease in Slovenia: A Nationwide Study","volume":"2015","author":"Urlep","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1053\/j.gastro.2008.06.081","article-title":"Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease","volume":"135","author":"Russell","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.crohns.2009.07.001","article-title":"Frequency of indeterminate colitis in children and adults with IBD\u2014A metaanalysis","volume":"3","author":"Prenzel","year":"2009","journal-title":"J. Crohns Colitis"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1080\/00365520510012136","article-title":"Essential fatty acid depletion in children with inflammatory bowel disease","volume":"40","author":"Socha","year":"2005","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1053\/j.gastro.2014.07.023","article-title":"The diagnostic approach to monogenic very early onset inflammatory bowel disease","volume":"147","author":"Uhlig","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1097\/MPG.0000000000002205","article-title":"Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection and Other Conditions in Children: A Joint Position Paper from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition","volume":"68","author":"Davidovics","year":"2019","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1097\/MPG.0000000000002141","article-title":"Use of Biosimilars in Paediatric Inflammatory Bowel Disease: An Updated Position Statement of the Paediatric IBD Porto Group of ESPGHAN","volume":"68","author":"Assa","year":"2019","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1097\/MPG.0000000000002092","article-title":"Endoscopy in Pediatric Inflammatory Bowel Disease: A Position Paper on Behalf of the Porto IBD Group of the Espghan","volume":"67","author":"Oliva","year":"2018","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1097\/MPG.0000000000001982","article-title":"Paediatric Intestinal Pseudo-Obstruction: Evidence and Consensus-Based Recommendations from an ESPGHAN-Led Expert Group","volume":"66","author":"Thapar","year":"2018","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1097\/MPG.0000000000002035","article-title":"Management of Paediatric Ulcerative Colitis, Part 1: Ambulatory Care\u2014An Evidence-Based Guideline from ECCO and ESPGHAN","volume":"67","author":"Turner","year":"2018","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1097\/MPG.0000000000002036","article-title":"Management of Paediatric Ulcerative Colitis, Part 2: Acute Severe Colitis; An Evidence-based Consensus Guideline from ECCO and ESPGHAN","volume":"67","author":"Turner","year":"2018","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.3748\/wjg.v19.i14.2217","article-title":"Evolution of disease phenotype in adult and pediatric onset Crohn\u2019s disease in a population-based cohort","volume":"19","author":"Lovasz","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s12016-018-8689-9","article-title":"Gastrointestinal Disorders Associated with Primary Immunodeficiency Diseases","volume":"57","author":"Hartono","year":"2018","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1093\/ibd\/izz178","article-title":"Diagnostic Approach to Monogenic Inflammatory Bowel Disease in Clinical Practice: A Ten-Year Multicentric Experience","volume":"26","author":"Lega","year":"2020","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2208","DOI":"10.1053\/j.gastro.2020.02.023","article-title":"Prevalence and Clinical Features of Inflammatory Bowel Diseases Associated with Monogenic Variants, Identified by Whole-Exome Sequencing in 1000 Children at a Single Center","volume":"158","author":"Crowley","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e00129","DOI":"10.14309\/ctg.0000000000000129","article-title":"Genetic Sequencing of Pediatric Patients Identifies Mutations in Monogenic Inflammatory Bowel Disease Genes that Translate to Distinct Clinical Phenotypes","volume":"11","author":"Ashton","year":"2020","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/nature11582","article-title":"Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease","volume":"491","author":"Jostins","year":"2012","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kenny, E.E., Pe\u2019er, I., Karban, A., Ozelius, L., Mitchell, A.A., Ng, S.M., Erazo, M., Ostrer, H., Abraham, C., and Abreu, M.T. (2012). A genome-wide scan of Ashkenazi Jewish Crohn\u2019s disease suggests novel susceptibility loci. PLoS Genet., 8.","DOI":"10.1371\/journal.pgen.1002559"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1053\/j.gastro.2012.12.021","article-title":"A genome-wide association study identifies 2 susceptibility Loci for Crohn\u2019s disease in a Japanese population","volume":"144","author":"Yamazaki","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1136\/gutjnl-2013-305193","article-title":"Genome-wide association study of Crohn\u2019s disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations","volume":"63","author":"Yang","year":"2014","journal-title":"Gut"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/ng.3359","article-title":"Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations","volume":"47","author":"Liu","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1038\/ng.3528","article-title":"Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci","volume":"48","author":"Ellinghaus","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/ng.3760","article-title":"Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease","volume":"49","author":"Moutsianas","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1159\/000228555","article-title":"Genetic determinants of pediatric inflammatory bowel disease: Is age of onset genetically determined?","volume":"27","author":"Scherr","year":"2009","journal-title":"Dig. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"39831","DOI":"10.1038\/srep39831","article-title":"Genetic architecture differences between pediatric and adult-onset inflammatory bowel diseases in the Polish population","volume":"6","author":"Ostrowski","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/S0140-6736(15)00465-1","article-title":"Inherited determinants of Crohn\u2019s disease and ulcerative colitis phenotypes: A genetic association study","volume":"387","author":"Cleynen","year":"2016","journal-title":"Lancet"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1093\/ibd\/izx084","article-title":"Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis","volume":"24","author":"Venkateswaran","year":"2018","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/nature08494","article-title":"Finding the missing heritability of complex diseases","volume":"461","author":"Manolio","year":"2009","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1093\/glycob\/cwy015","article-title":"Glycosyltransferase genes that cause monogenic congenital disorders of glycosylation are distinct from glycosyltransferase genes associated with complex diseases","volume":"28","author":"Joshi","year":"2018","journal-title":"Glycobiology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1097\/ACI.0000000000000486","article-title":"Very early onset IBD: Novel genetic aetiologies","volume":"18","author":"Batura","year":"2018","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1038\/ng.952","article-title":"Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease","volume":"43","author":"Rivas","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nature22969","article-title":"Fine-mapping inflammatory bowel disease loci to single-variant resolution","volume":"547","author":"Huang","year":"2017","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"D754","DOI":"10.1093\/nar\/gkx1098","article-title":"Ensembl 2018","volume":"46","author":"Zerbino","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/ng.2653","article-title":"The Genotype-Tissue Expression (GTEx) project","volume":"45","author":"Lonsdale","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"D457","DOI":"10.1093\/nar\/gkv1070","article-title":"KEGG as a reference resource for gene and protein annotation","volume":"44","author":"Kanehisa","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1093\/bioinformatics\/btp101","article-title":"ClueGO: A Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks","volume":"25","author":"Bindea","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s10875-016-0339-5","article-title":"Targeted Sequencing and Immunological Analysis Reveal the Involvement of Primary Immunodeficiency Genes in Pediatric IBD: A Japanese Multicenter Study","volume":"37","author":"Suzuki","year":"2017","journal-title":"J. Clin. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1093\/ecco-jcc\/jjy068","article-title":"Diagnostic Yield of Next-Generation Sequencing in Very Early-Onset Inflammatory Bowel Diseases: A Multicenter Study","volume":"12","author":"Parlato","year":"2018","journal-title":"J. Crohns Colitis"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41435-018-0015-2","article-title":"Genetic variants and pathways implicated in a pediatric inflammatory bowel disease cohort","volume":"20","author":"Shaw","year":"2019","journal-title":"Genes Immun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1097\/MIB.0000000000000775","article-title":"Microbiota-specific Th17 Cells: Yin and Yang in Regulation of Inflammatory Bowel Disease","volume":"22","author":"Wu","year":"2016","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1126\/science.1172702","article-title":"CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner","volume":"326","author":"Chaudhry","year":"2009","journal-title":"Science"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Van Lierop, P.P., Swagemakers, S.M., de Bie, C.I., Middendorp, S., van Baarlen, P., Samsom, J.N., van Ijcken, W.F., Escher, J.C., van der Spek, P.J., and Nieuwenhuis, E.E. (2013). Gene expression analysis of peripheral cells for subclassification of pediatric inflammatory bowel disease in remission. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079549"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1136\/gutjnl-2011-301668","article-title":"Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn\u2019s disease: Unexpected results of a randomised, double-blind placebo-controlled trial","volume":"61","author":"Hueber","year":"2012","journal-title":"Gut"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/mi.2011.24","article-title":"IL-17: Intestinal effector or protector?","volume":"4","author":"Fuss","year":"2011","journal-title":"Mucosal Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.immuni.2015.09.003","article-title":"Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability","volume":"43","author":"Lee","year":"2015","journal-title":"Immunity"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Brockmann, L., Giannou, A.D., Gagliani, N., and Huber, S. (2017). Regulation of TH17 Cells and Associated Cytokines in Wound Healing, Tissue Regeneration, and Carcinogenesis. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18051033"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"G479","DOI":"10.1152\/ajpgi.00208.2019","article-title":"IFN-\u03b3 and IL-17A regulate intestinal crypt production of CXCL10 in the healthy and inflamed colon","volume":"318","author":"Walrath","year":"2020","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Smith, M.K., Pai, J., Panaccione, R., Beck, P., Ferraz, J.G., and Jijon, H. (2019). Crohn\u2019s-like disease in a patient exposed to anti-Interleukin-17 blockade (Ixekizumab) for the treatment of chronic plaque psoriasis: A case report. BMC Gastroenterol., 19.","DOI":"10.1186\/s12876-019-1067-0"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1053\/j.gastro.2020.01.001","article-title":"Safety of Janus Kinase Inhibitors in Patients with Inflammatory Bowel Diseases or Other Immune-mediated Diseases: A Systematic Review and Meta-Analysis","volume":"158","author":"Olivera","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/s41575-020-0273-0","article-title":"JAK-STAT pathway targeting for the treatment of inflammatory bowel disease","volume":"17","author":"Salas","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/10\/4\/243\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:37:29Z","timestamp":1760179049000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/10\/4\/243"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,26]]},"references-count":53,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["jpm10040243"],"URL":"https:\/\/doi.org\/10.3390\/jpm10040243","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,26]]}}}