Genome-Wide DNA Methylation Identifies Potential Disease-Specific Biomarkers and Pathophysiologic Mechanisms in Irritable Bowel Syndrome, Inflammatory Bowel Disease, and Celiac Disease

Swapna Mahurkar-Joshi; Mike Thompson; Elizza Villarruel; James D Lewis; Lisa D Lin; Mary Farid; Hamed Nayeb-Hashemi; Tina Storage; Guy A Weiss; Berkeley N Limketkai; Jenny S Sauk; Emeran A Mayer; Lin Chang

doi:10.1111/nmo.14980

Genome-Wide DNA Methylation Identifies Potential Disease-Specific Biomarkers and Pathophysiologic Mechanisms in Irritable Bowel Syndrome, Inflammatory Bowel Disease, and Celiac Disease

Neurogastroenterol Motil. 2024 Dec 13:e14980. doi: 10.1111/nmo.14980. Online ahead of print.

Authors

Swapna Mahurkar-Joshi^{1

2

3}, Mike Thompson⁴, Elizza Villarruel³, James D Lewis⁵, Lisa D Lin^{2

3}, Mary Farid^{2

3}, Hamed Nayeb-Hashemi^{2

3}, Tina Storage^{2

3}, Guy A Weiss^{2

3

6}, Berkeley N Limketkai^{2

3}, Jenny S Sauk^{2

3}, Emeran A Mayer^{1

2

3}, Lin Chang^{1

2

3}

Affiliations

¹ G. Oppenheimer Center for the Neurobiology of Stress and Resilience, Los Angeles, California, USA.
² Vatche and Tamar Manoukian Division of Digestive Diseases, Los Angeles, California, USA.
³ David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁴ Systems Biology, Centre for Genomic Regulation, Barcelona, Spain.
⁵ Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁶ UCLA Celiac Disease Program, Los Angeles, California, USA.

PMID: 39673136
DOI: 10.1111/nmo.14980

Abstract

Background and aims: Irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and celiac disease (CeD) present with similar gastrointestinal (GI) symptoms. DNA methylation-based 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-based classifiers, and identify associated gene ontology (GO) terms.

Methods: Genome-wide 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-validation controlling for confounders. Functional enrichment was assessed using GO.

Results: Three hundred and fifteen participants (148 IBS, 47 IBD, 34 CeD, and 86 HC) had DNA methylation data. IBS-IBD and IBD-CeD showed the highest number of differentially methylated CpG sites followed by IBD-HC, CeD-HC, and IBS-HC. IBS-associated genes were enriched in cell adhesion and neuronal pathways, while IBD- and CeD-associated markers were enriched in inflammation and MHC class II pathways, respectively (p < 0.05). Classification performances assessed using area under the receiver operating characteristic curves (AUC) for IBS-IBD, IBS-CeD, and IBD-CeD were 0.80 (95% CI = 0.7-0.87, p = 6.75E-10), 0.78 (95% CI = 0.68-0.86, p = 4.57E-10), and 0.73 (95% CI = 0.62-0.83, p = 0.03), respectively. The performance of IBD-HC was successfully validated using external data (AUC = 0.74 [95% CI = 68-0.80, p < 0.001]).

Conclusions: Blood-based DNA methylation biomarkers can potentially distinguish chronic GI disorders that present with similar symptoms. GO suggested functional significance of the classifiers in disease-specific pathology.

Keywords: Celiac Disease; DNA Methylation‐Based Biomarkers; Inflammatory Bowel Disease; Irritable Bowel Syndrome; Machine Learning.

Abstract

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