炎症性肠病循环转录组特征分析提供了多个转录因子失调的证据，包括 NFE2、SPI1、CEBPB 和 IRF2。
Characterisation of the Circulating Transcriptomic Landscape in Inflammatory Bowel Disease Provides Evidence for Dysregulation of Multiple Transcription Factors Including NFE2, SPI1, CEBPB, and IRF2.
机构信息
Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland.
出版信息
J Crohns Colitis. 2022 Aug 30;16(8):1255-1268. doi: 10.1093/ecco-jcc/jjac033.
AIM
To assess the pathobiological and translational importance of whole-blood transcriptomic analysis in inflammatory bowel disease [IBD].
METHODS
We analysed whole-blood expression profiles from paired-end sequencing in a discovery cohort of 590 Europeans recruited across six countries in the IBD Character initiative (newly diagnosed patients with Crohn's disease [CD; n = 156], ulcerative colitis [UC; n = 167], and controls [n = 267]), exploring differential expression [DESeq2], co-expression networks [WGCNA], and transcription factor involvement [EPEE, ChEA, DoRothEA]. Findings were validated by analysis of an independent replication cohort [99 CD, 100 UC, 95 controls]. In the discovery cohort, we also defined baseline expression correlates of future treatment escalation using cross-validated elastic-net and random forest modelling, along with a pragmatic ratio detection procedure.
RESULTS
Disease-specific transcriptomes were defined in IBD [8697 transcripts], CD [7152], and UC [8521], with the most highly significant changes in single genes, including CD177 (log2-fold change [LFC] = 4.63, p = 4.05 × 10-118), MCEMP1 [LFC = 2.45, p = 7.37 × 10-109], and S100A12 [LFC = 2.31, p = 2.15 × 10-93]. Significantly over-represented pathways included IL-1 [p = 1.58 × 10-11], IL-4, and IL-13 [p = 8.96 × 10-9]. Highly concordant results were obtained using multiple regulatory activity inference tools applied to the discovery and replication cohorts. These analyses demonstrated central roles in IBD for the transcription factors NFE2, SPI1 [PU.1], CEBPB, and IRF2, all regulators of cytokine signalling, based on a consistent signal across cohorts and transcription factor ranking methods. A number of simple transcriptome-based models were associated with the need for treatment escalation, including the binary CLEC5A/CDH2 expression ratio in UC (hazard ratio = 23.4, 95% confidence interval [CI] 5.3-102.0).
CONCLUSIONS
Transcriptomic analysis has allowed for a detailed characterisation of IBD pathobiology, with important potential translational implications.
目的
评估全血转录组分析在炎症性肠病（IBD）中的病理生物学和转化意义。
方法
我们分析了来自 6 个国家 IBD 特征研究计划中招募的 590 名欧洲人配对端测序的全血表达谱（新诊断为克罗恩病[CD]的患者[156 例]、溃疡性结肠炎[UC]的患者[167 例]和对照组[267 例]），探索差异表达[DESeq2]、共表达网络[WGCNA]和转录因子参与[EPEE、ChEA、DoRothEA]。通过对独立复制队列[99 例 CD、100 例 UC、95 例对照]的分析验证了这些发现。在发现队列中，我们还使用交叉验证弹性网络和随机森林模型以及实用比率检测程序，定义了未来治疗升级的基线表达相关性。
结果
在 IBD[8697 个转录本]、CD[7152 个]和 UC[8521 个]中定义了疾病特异性转录组，单个基因的变化最为显著，包括 CD177（对数倍变化[LFC]=4.63，p=4.05×10-118）、MCEMP1[LFC=2.45，p=7.37×10-109]和 S100A12[LFC=2.31，p=2.15×10-93]。过度表达的途径包括 IL-1[p=1.58×10-11]、IL-4 和 IL-13[p=8.96×10-9]。使用多种调节活性推断工具应用于发现和复制队列，得到了高度一致的结果。这些分析表明，转录因子 NFE2、SPI1[PU.1]、CEBPB 和 IRF2 在 IBD 中具有核心作用，它们都是细胞因子信号的调节剂，这是基于各队列和转录因子排序方法的一致信号。一些简单的基于转录组的模型与治疗升级的需要相关，包括 UC 中 CLEC5A/CDH2 表达比（危险比=23.4，95%置信区间[CI]5.3-102.0）。
结论
转录组分析允许对 IBD 病理生物学进行详细描述，具有重要的潜在转化意义。
Zotero 插件