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Molecular Characterization of Limited Ulcerative Colitis Reveals Novel Biology and Predictors of Disease Extension
Gastroenterology ( IF 25.7 ) Pub Date : 2021-09-02 , DOI: 10.1053/j.gastro.2021.08.053
Carmen Argmann 1 , Minami Tokuyama 2 , Ryan C Ungaro 2 , Ruiqi Huang 3 , Ruixue Hou 3 , Sakteesh Gurunathan 2 , Roman Kosoy 1 , Antonio Di'Narzo 4 , Wenhui Wang 1 , Bojan Losic 1 , Haritz Irizar 5 , Lauren Peters 1 , Aleksandar Stojmirovic 6 , Gabrielle Wei 1 , Phillip H Comella 1 , Mark Curran 6 , Carrie Brodmerkel 6 , Joshua R Friedman 6 , Ke Hao 4 , Eric E Schadt 4 , Jun Zhu 4 , Judy Cho 2 , Noam Harpaz 7 , Marla C Dubinsky 2 , Bruce E Sands 2 , Andrew Kasarskis 8 , Saurabh Mehandru 2 , Jean-Frederic Colombel 2 , Mayte Suárez-Fariñas 9
Affiliation  

Background And Aims

Disease extent varies in ulcerative colitis (UC) from proctitis to left-sided colitis to pancolitis and is a major prognostic factor. When the extent of UC is limited there is often a sharp demarcation between macroscopically involved and uninvolved areas and what defines this or subsequent extension is unknown. We characterized the demarcation site molecularly and determined genes associated with subsequent disease extension.

Methods

We performed RNA sequence analysis of biopsy specimens from UC patients with endoscopically and histologically confirmed limited disease, of which a subset later extended. Biopsy specimens were obtained from the endoscopically inflamed upper (proximal) limit of disease, immediately adjacent to the uninvolved colon, as well as at more proximal, endoscopically uninflamed colonic segments.

Results

Differentially expressed genes were identified in the endoscopically inflamed biopsy specimens taken at each patient’s most proximal diseased site relative to healthy controls. Expression of these genes in the more proximal biopsy specimens transitioned back to control levels abruptly or gradually, the latter pattern supporting the concept that disease exists beyond the endoscopic disease demarcation site. The gradually transitioning genes were associated with inflammation, angiogenesis, glucuronidation, and homeodomain pathways. A subset of these genes in inflamed biopsy specimens was found to predict disease extension better than clinical features and were responsive to biologic therapies. Network analysis revealed critical roles for interferon signaling in UC inflammation and poly(ADP-ribose) polymerase 14 (PARP14) was a predicted key driver gene of extension. Higher PARP14 protein levels were found in inflamed biopsy specimens of patients with limited UC that subsequently extended.

Conclusion

Molecular predictors of disease extension reveal novel strategies for disease prognostication and potential therapeutic targeting.



中文翻译:

有限溃疡性结肠炎的分子特征揭示了疾病扩展的新生物学和预测因子

背景和目标

溃疡性结肠炎 (UC) 的疾病程度从直肠炎到左侧结肠炎再到全结肠炎不等,是主要的预后因素。当 UC 的范围受到限制时,通常在宏观受累区域和未受累区域之间存在明显的界限,并且不知道是什么定义了这种或随后的扩展。我们在分子上对分界点进行了表征,并确定了与随后的疾病扩展相关的基因。

方法

我们对 UC 患者的活检标本进行了 RNA 序列分析,这些患者经内镜和组织学证实为局限性疾病,后来扩展了其中的一个子集。活检标本取自内窥镜下发炎的疾病上限(近端),紧邻未受累的结肠,以及更近端的内窥镜下未发炎的结肠段。

结果

相对于健康对照,在每位患者最近的病变部位采集的内窥镜发炎活检标本中鉴定出差异表达的基因。这些基因在更近端的活检标本中的表达突然或逐渐转变回控制水平,后一种模式支持疾病存在于内窥镜疾病分界部位之外的概念。逐渐转变的基因与炎症、血管生成、葡萄糖醛酸化和同源域途径有关。在发炎的活检标本中发现这些基因的一个子集比临床特征更好地预测疾病扩展并且对生物疗法有反应。网络分析揭示了干扰素信号传导在 UC 炎症中的关键作用,聚(ADP-核糖)聚合酶 14 (PARP14) 是预测的扩展关键驱动基因。在随后扩展的有限 UC 患者的发炎活检标本中发现更高的 PARP14 蛋白水平。

结论

疾病扩展的分子预测因子揭示了疾病预后和潜在治疗靶向的新策略。

更新日期:2021-09-02
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