克罗恩病和溃疡性结肠炎有两种分子亚型,其发病机制和药物反应各不相同。

Jing Wang, Heath Guay, Dan Chang
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引用次数: 0

摘要

背景和目的:目前已批准多种疗法治疗克罗恩病(CD)和溃疡性结肠炎(UC),这表明这两种疾病可能具有相同的分子亚型。本研究旨在确定具有共同疾病分子驱动因素的共同患者亚型:方法:对包含 406 个 CD 和 421 个 UC 样本的五个公共数据集进行整合,以确定分子亚型。然后,对来自六个独立数据集和八个治疗数据集的患者标签进行预测,以验证亚型并确定与皮质类固醇、英夫利昔单抗、维妥珠单抗和乌斯特库木单抗反应状态的关系:从训练数据集中确定了两种分子亚型,其中CD和UC患者在每种亚型中的比例相对平均。我们发现了与先天性/适应性免疫反应和组织重塑相关的六个 S1 特异性基因模块和九种 S1 特异性细胞类型(循环 T、Tregs、cd8+ 固有膜、滤泡 B、循环 B 浆、炎性单核细胞、炎性成纤维细胞和毛细血管后静脉)。亚型 S2 与代谢功能相关的三个模块和四种细胞类型(未成熟肠细胞、转运扩增细胞、未成熟鹅口疮细胞和 WNT5B+)有关。基于 20 个基因分类器,这些亚型可在六个独立数据集中复制。此外,亚型 S2 对四种治疗方法的反应率明显高于亚型 S1:本研究发现并验证了CD和UC共有的基于转录组的稳健分子分类,并建立了20个基因的分类器。由于两个亚型的分子机制和药物反应不同,我们的分类可能有助于解读 IBD 患者的异质性分子和临床信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Crohn's disease and ulcerative colitis share two molecular subtypes with different mechanisms and drug response.

Background and aims: Several therapies have been approved to treat crohn's disease (CD) and ulcerative colitis (UC), indicating that both diseases may share the same molecular subtypes. The aim of this study is to identify shared patient subtypes with common molecular drivers of disease.

Methods: Five public datasets with 406 CD and 421 UC samples were integrated to identify molecular subtypes. Then, the patient labels from six independent datasets and eight treatment datasets were predicted for validating subtypes and identifying the relationship with response status of corticosteroids, infliximab, vedolizumab, and ustekimumab.

Results: Two molecular subtypes were identified from the training datasets, in which CD and UC patients were relatively evenly represented in each subtype. We found six S1-specific gene modules related to innate/adaptive immune responses and tissue remodeling and nine S1-specific cell types (cycling T, Tregs, cd8+ lamina propria, follicular B, cycling B plasma, inflammatory monocytes, inflammatory fibroblast, and post-capillary venules). Subtype S2 was associated with three modules related to metabolism functions and four cell types (immature enterocytes, transit amplifying, immature goblet and WNT5B+). The subtypes can be replicated in six independent datasets based on a 20-gene classifier. Furthermore, response rates to four treatments in subtype S2 were significantly higher than those in subtype S1.

Conclusions: This study discovered and validated a robust transcriptome-based molecular classification shared by CD and UC and built a 20-gene classifier. Because two subtypes have different molecular mechanisms and drug response, our classification may aid interpretation of heterogeneous molecular and clinical information in IBD patients.

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