Whole blood expression profiling from the TREAT trial: insights for the pathogenesis of polyarticular juvenile idiopathic arthritis.
Whole blood expression profiling from the TREAT trial: insights for the pathogenesis of polyarticular juvenile idiopathic arthritis.
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DOI：
10.1186/s13075-016-1059-1
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发表时间：
2016-07-07
影响因子：
4.9
通讯作者：
Jarvis JN
中科院分区：
文献类型：
--
作者：
Jiang K;Wong L;Sawle AD;Frank MB;Chen Y;Wallace CA;Jarvis JN
青少年特发性关节炎的早期攻击性治疗试验(TREAT试验)伴随着一代人一次的翻译研究样本收集。在本文中，我们报道了全血基因表达分析和基因组数据挖掘的结果，旨在揭示多关节幼年特发性关节炎(JIA)的免疫发病机制。治疗样本和来自独立队列的样本在Affymetrix微阵列上进行分析，并与健康对照组进行比较。来自独立队列的数据被用来验证处理数据。用通路分析来表征基因表达谱。此外，我们将差异基因表达与基因组中功能调控元件的新信息联系起来，以建立JIA中异常基因表达的模型。在处理样本和独立队列之间的基因表达有很强的一致性。此外，类风湿因子(RF)阳性和RF阴性的患者在全血表达谱上只有很小的差异。对组合样本的分析显示，176个探针代表了158个基因，显示了基线水平的治疗对象和健康对照组之间的差异表达。没有一个差异表达的基因编码在包含单核苷酸多态的连锁不平衡块中，这些单核苷酸多态与JIA的风险相关。对这些基因的功能分析显示了与先天免疫和获得性免疫相关的多个过程的功能关联，并且似乎反映了STAT1-3/干扰素反应因子介导的通路的总体抑制。尽管有其局限性，但全血表达谱清楚地将多关节JIA儿童与健康对照组区分开来。全血表达谱确定了几条与生物相关的免疫途径，需要在同质细胞群体中进行研究，以阐明发病机制。ClinicalTrials.gov注册号NCT00443430，最初注册于2007年3月2日，最近一次更新为2013年5月30日。
The Trial of Early Aggressive Therapy in Juvenile Idiopathic Arthritis (TREAT trial) was accompanied by a once-in-a-generation sample collection for translational research. In this paper, we report the results of whole blood gene expression analyses and genomic data-mining designed to cast light on the immunopathogenesis of polyarticular juvenile idiopathic arthritis (JIA). TREAT samples and samples from an independent cohort were analyzed on Affymetrix microarrays and compared to healthy controls. Data from the independent cohort were used to validate the TREAT data. Pathways analysis was used to characterize gene expression profiles. Furthermore, we correlated differential gene expression with new information about functional regulatory elements within the genome to develop models of aberrant gene expression in JIA. There was a strong concordance in gene expression between TREAT samples and the independent cohort. In addition, rheumatoid factor (RF)-positive and RF-negative patients showed only small differences on whole blood expression profiles. Analysis of the combined samples showed 158 genes represented by 176 probes that showed differential expression between TREAT subjects at baseline and healthy controls. None of the differentially expressed genes were encoded within linkage disequilibrium blocks containing single nucleotide polymorphisms known to be associated with risk for JIA. Functional analysis of these genes showed functional associations with multiple processes associated with innate and adaptive immunity, and appeared to reflect overall suppression of STAT1–3/interferon response factor-mediated pathways. Despite their limitations, whole blood expression profiles clearly distinguish children with polyarticular JIA from healthy controls. Whole blood expression profiles identify several immunologic pathways of biologic relevance that will need to be pursued in homogeneous cell populations in order to clarify mechanisms of pathogenesis. ClinicalTrials.gov registry #NCT00443430, originally registered 2 March 2007 and last updated 30 May 2013.