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
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引用次数: 0
摘要
背景和目的: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用于这些疾病的分类研究。我们旨在研究 IBS、IBD、CeD 和健康对照(HC)的 DNA 甲基化图谱,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:使用 Illumina 的 450K 或 EPIC 阵列测量了 315 名 IBS、IBD、CeD 和 HC 患者外周血单核细胞的全基因组 DNA 甲基化情况。304 例 IBD 和 HC 样本的甲基化数据集用于外部验证。差异甲基化使用一般线性模型进行测量。分类器是使用惩罚性广义线性模型开发的,使用双重交叉验证控制混杂因素。使用 GO 对功能富集性进行评估:315 名参与者(148 名 IBS、47 名 IBD、34 名 CeD 和 86 名 HC)有 DNA 甲基化数据。IBS-IBD和IBD-CeD显示了最多的不同甲基化CpG位点,其次是IBD-HC、CeD-HC和IBS-HC。IBS 相关基因富集在细胞粘附和神经元通路中,而 IBD 和 CeD 相关标记物则分别富集在炎症和 MHC II 类通路中(P 结论):基于血液的 DNA 甲基化生物标记物有可能区分症状相似的慢性消化道疾病。GO提示了分类器在特定疾病病理学中的功能意义。
Genome-Wide DNA Methylation Identifies Potential Disease-Specific Biomarkers and Pathophysiologic Mechanisms in Irritable Bowel Syndrome, Inflammatory Bowel Disease, and Celiac Disease.
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.
期刊介绍:
Neurogastroenterology & Motility (NMO) is the official Journal of the European Society of Neurogastroenterology & Motility (ESNM) and the American Neurogastroenterology and Motility Society (ANMS). It is edited by James Galligan, Albert Bredenoord, and Stephen Vanner. The editorial and peer review process is independent of the societies affiliated to the journal and publisher: Neither the ANMS, the ESNM or the Publisher have editorial decision-making power. Whenever these are relevant to the content being considered or published, the editors, journal management committee and editorial board declare their interests and affiliations.