全基因组DNA甲基化鉴定肠易激综合征、炎症性肠病和乳糜泻中潜在的疾病特异性生物标志物和病理生理机制。

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

作者信息

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

机构信息

G. Oppenheimer Center for the Neurobiology of Stress and Resilience, Los Angeles, California, USA.

Vatche and Tamar Manoukian Division of Digestive Diseases, Los Angeles, California, USA.

出版信息

Neurogastroenterol Motil. 2025 Feb;37(2):e14980. doi: 10.1111/nmo.14980. Epub 2024 Dec 13.

DOI:10.1111/nmo.14980

PMID:39673136

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11748828/

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.

摘要

背景与目的

肠易激综合征（IBS）、炎症性肠病（IBD）和乳糜泻（CeD）具有相似的胃肠道（GI）症状。基于DNA甲基化的生物标志物尚未作为诊断生物标志物来区分这些疾病。我们旨在研究IBS、IBD、CeD和健康对照（HC）的DNA甲基化谱，开发基于机器学习的分类器，并确定相关的基因本体（GO）术语。

方法

使用Illumina的450K或EPIC芯片检测315例IBS、IBD、CeD患者和HC的外周血单个核细胞的全基因组DNA甲基化。304例IBD和HC样本的甲基化数据集用于外部验证。使用一般线性模型测量差异甲基化。使用惩罚广义线性模型并通过双重交叉验证控制混杂因素来开发分类器。使用GO评估功能富集。

结果

315名参与者（148例IBS、47例IBD、34例CeD和86例HC）有DNA甲基化数据。IBS-IBD和IBD-CeD显示差异甲基化CpG位点数量最多，其次是IBD-HC、CeD-HC和IBS-HC。与IBS相关的基因在细胞黏附和神经元途径中富集，而与IBD和CeD相关的标志物分别在炎症和MHC II类途径中富集（p<0.05）。使用受试者工作特征曲线下面积（AUC）评估的IBS-IBD、IBS-CeD和IBD-CeD的分类性能分别为0.80（95%CI=0.7-0.87，p=6.75E-10）、0.78（95%CI=0.68-0.86，p=4.57E-10）和0.73（95%CI=0.62-0.83，p=0.03）。IBD-HC的性能使用外部数据成功验证（AUC=0.74[95%CI=68-0.80，p<0.001]）。