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DNA methylation\u2010based biomarkers have not been investigated as diagnostic biomarkers to classify these disorders. We aimed to study DNA methylation profiles of IBS, IBD, CeD, and healthy controls (HC), develop machine learning\u2010based classifiers, and identify associated gene ontology (GO) terms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Genome\u2010wide DNA methylation of peripheral blood mononuclear cells from 315 patients with IBS, IBD, CeD, and HC was measured using Illumina's 450K or EPIC arrays. A methylation dataset on 304 IBD and HC samples was used for external validation. Differential methylation was measured using general linear models. Classifiers were developed using penalized generalized linear models using double cross\u2010validation controlling for confounders. Functional enrichment was assessed using GO.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Three hundred and fifteen participants (148 IBS, 47 IBD, 34 CeD, and 86 HC) had DNA methylation data. IBS\u2010IBD and IBD\u2010CeD showed the highest number of differentially methylated CpG sites followed by IBD\u2010HC, CeD\u2010HC, and IBS\u2010HC. IBS\u2010associated genes were enriched in cell adhesion and neuronal pathways, while IBD\u2010 and CeD\u2010associated markers were enriched in inflammation and MHC class II pathways, respectively (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Classification performances assessed using area under the receiver operating characteristic curves (AUC) for IBS\u2010IBD, IBS\u2010CeD, and IBD\u2010CeD were 0.80 (95% CI\u2009=\u20090.7\u20130.87, <jats:italic>p<\/jats:italic>\u2009=\u20096.75E\u201010), 0.78 (95% CI\u2009=\u20090.68\u20130.86, <jats:italic>p<\/jats:italic>\u2009=\u20094.57E\u201010), and 0.73 (95% CI\u2009=\u20090.62\u20130.83, <jats:italic>p<\/jats:italic>\u2009=\u20090.03), respectively. The performance of IBD\u2010HC was successfully validated using external data (AUC\u2009=\u20090.74 [95% CI\u2009=\u200968\u20130.80, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001]).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Blood\u2010based DNA methylation biomarkers can potentially distinguish chronic GI disorders that present with similar symptoms. GO suggested functional significance of the classifiers in disease\u2010specific pathology.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nmo.14980","type":"journal-article","created":{"date-parts":[[2024,12,14]],"date-time":"2024-12-14T06:35:13Z","timestamp":1734158113000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Genome\u2010Wide <scp>DNA<\/scp> Methylation Identifies Potential Disease\u2010Specific Biomarkers and Pathophysiologic Mechanisms in Irritable Bowel Syndrome, Inflammatory Bowel Disease, and Celiac Disease"],"prefix":"10.1111","volume":"37","author":[{"given":"Swapna","family":"Mahurkar\u2010Joshi","sequence":"first","affiliation":[{"name":"G. Oppenheimer Center for the Neurobiology of Stress and Resilience  Los Angeles California USA"},{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases  Los Angeles California USA"},{"name":"David Geffen School of Medicine at UCLA  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Thompson","sequence":"additional","affiliation":[{"name":"Systems Biology Centre for Genomic Regulation  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizza","family":"Villarruel","sequence":"additional","affiliation":[{"name":"David Geffen School of Medicine at UCLA  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa D.","family":"Lin","sequence":"additional","affiliation":[{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases  Los Angeles California USA"},{"name":"David Geffen School of Medicine at UCLA  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Farid","sequence":"additional","affiliation":[{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases  Los Angeles California USA"},{"name":"David Geffen School of Medicine at UCLA  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamed","family":"Nayeb\u2010Hashemi","sequence":"additional","affiliation":[{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases  Los Angeles California USA"},{"name":"David Geffen School of Medicine at UCLA  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Storage","sequence":"additional","affiliation":[{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases  Los Angeles California USA"},{"name":"David Geffen School of Medicine at UCLA  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy A.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases  Los Angeles California USA"},{"name":"David Geffen School of Medicine at UCLA  Los Angeles California USA"},{"name":"UCLA Celiac Disease Program  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berkeley N.","family":"Limketkai","sequence":"additional","affiliation":[{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases  Los Angeles California USA"},{"name":"David Geffen School of Medicine at UCLA  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny S.","family":"Sauk","sequence":"additional","affiliation":[{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases  Los Angeles California USA"},{"name":"David Geffen School of Medicine at UCLA  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emeran A.","family":"Mayer","sequence":"additional","affiliation":[{"name":"G. 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