Gene Expression Changes Associated with Resistance to Intravenous Corticosteroid Therapy in Children with Severe Ulcerative Colitis
Gene Expression Changes Associated with Resistance to Intravenous Corticosteroid Therapy in Children with Severe Ulcerative Colitis
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DOI：
10.1371/journal.pone.0013085
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发表时间：
2010-09-30
期刊：
影响因子：
3.7
通讯作者：
Silverberg, Mark S.
中科院分区：
文献类型：
--
作者：
Kabakchiev, Boyko;Turner, Dan;Silverberg, Mark S.
背景和目的：RNA表达的微阵列分析可以对炎症中的作用途径进行肉眼检查。我们的目标是确定在开始静脉注射糖皮质激素治疗后早期全血中的基因表达是否与应答相关。方法：从128例因静脉注射糖皮质激素治疗重症UC而住院的儿童患者中，我们选择了20例糖皮质激素应答(出院或第5天PUCAI45)进行分析。从静脉注射糖皮质激素治疗第3天采集的血样中提取总RNA。在Affymetrix Human gene 1.0 ST阵列上对洗脱的转录本进行定量。采用局部汇集误差法发现差异表达基因，并采用假发现率校正法调整多重比较。结果：共检测到41个差异表达基因。其中两个基因，CEACAM1和MMP8，可能被甲基强的松龙通过IL8抑制，在无反应的患者中都被发现过度表达。ABCC4(MRP4)是多药耐药超家族成员之一，是一种新的糖皮质激素耐药候选基因。从41个有意义的命中中挑选出10个基因的表达模式，能够对患者进行分类，敏感性和特异性分别为80%和80%。结论：参与炎症通路的几个基因的表达升高与治疗早期对静脉注射皮质类固醇治疗的抵抗有关。基因表达谱可能有助于对重症UC儿童静脉注射糖皮质激素的耐药性进行分类，并有助于临床治疗决策。
Background and Aims: Microarray analysis of RNA expression allows gross examination of pathways operative in inflammation. We aimed to determine whether genes expressed in whole blood early following initiation of intravenous corticosteroid treatment can be associated with response.Methods: From a prospectively accrued cohort of 128 pediatric patients hospitalized for intravenous corticosteroid treatment of severe UC, we selected for analysis 20 corticosteroid responsive (hospital discharge or PUCAI 45 by day 5). Total RNA was extracted from blood samples collected on day 3 of intravenous corticosteroid therapy. The eluted transcriptomes were quantified on Affymetrix Human Gene 1.0 ST arrays. The data was analysed by the local-pooled error method for discovery of differential gene expression and false discovery rate correction was applied to adjust for multiple comparisons.Results: A total of 41 genes differentially expressed between responders and non-responders were detected with statistical significance. Two of these genes, CEACAM1 and MMP8, possibly inhibited by methylprednisolone through IL8, were both found to be over-expressed in non-responsive patients. ABCC4 (MRP4) as a member of the multi-drug resistance superfamily was a novel candidate gene for corticosteroid resistance. The expression pattern of a cluster of 10 genes selected from the 41 significant hits were able to classify the patients with 80% sensitivity and 80% specificity.Conclusions: Elevated expression of several genes involved in inflammatory pathways was associated with resistance to intravenous corticosteroid therapy early in the course of treatment. Gene expression profiles may be useful to classify resistance to intravenous corticosteroids in children with severe UC and assist with clinical management decisions.