Network-based analysis reveals novel gene signatures in peripheral blood of patients with chronic obstructive pulmonary disease.
Network-based analysis reveals novel gene signatures in peripheral blood of patients with chronic obstructive pulmonary disease.
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DOI：
10.1186/s12931-017-0558-1
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发表时间：
2017-04-24
影响因子：
5.8
通讯作者：
Sin DD
中科院分区：
文献类型：
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作者：
Obeidat M;Nie Y;Chen V;Shannon CP;Andiappan AK;Lee B;Rotzschke O;Castaldi PJ;Hersh CP;Fishbane N;Ng RT;McManus B;Miller BE;Rennard S;Paré PD;Sin DD
慢性阻塞性肺疾病（COPD）目前是第三大死亡原因，并且存在识别外周血中的疾病生物标志物的巨大未满足的临床需求。与基因水平的差异表达方法来识别基因签名相比，网络分析提供了一种生物直观的方法，该方法利用转录组中的共表达模式来识别共表达基因的模块。应用加权基因共表达网络分析（WGCNA）对238例COPD患者外周血转录组进行分析，以发现共表达的基因模块。然后，我们确定这些模块之间的关系和用力呼气量在1秒（FEV 1）。在第二个独立队列的381名受试者中，我们确定了这些模块的保存及其与FEV 1的关系。对于那些与FEV 1显著相关的模块，我们使用额外的外部数据集确定了生物学过程以及过度代表的血细胞特异性基因表达。使用WGCNA，我们在发现队列中鉴定了共表达基因的17个模块。其中3个模块与FEV 1显著相关（FDR < 0.1）。在重复队列中，这些模块高度保留，并且它们的FEV 1相关性是可重复的（P < 0.05）。三个模块中的两个与FEV 1呈负相关，并富含IL 8和IL 10途径，与嗜中性粒细胞特异性基因表达相关。另一方面，正相关模块在DNA转录和翻译中富集，并且与CD 4+、CD 8 + T细胞特异性基因表达强烈相关。基于网络的方法是识别COPD潜在生物标志物的有前途的工具。ECLIPSE研究由葛兰素史克公司资助，编号为NCT 00292552和SCO 104960。本文的在线版本（doi：10.1186/s12931-017-0558-1）包含补充材料，可供授权用户使用。ClinicalTrials.gov
Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death and there is a huge unmet clinical need to identify disease biomarkers in peripheral blood. Compared to gene level differential expression approaches to identify gene signatures, network analyses provide a biologically intuitive approach which leverages the co-expression patterns in the transcriptome to identify modules of co-expressed genes. A weighted gene co-expression network analysis (WGCNA) was applied to peripheral blood transcriptome from 238 COPD subjects to discover co-expressed gene modules. We then determined the relationship between these modules and forced expiratory volume in 1 s (FEV1). In a second, independent cohort of 381 subjects, we determined the preservation of these modules and their relationship with FEV1. For those modules that were significantly related to FEV1, we determined the biological processes as well as the blood cell-specific gene expression that were over-represented using additional external datasets. Using WGCNA, we identified 17 modules of co-expressed genes in the discovery cohort. Three of these modules were significantly correlated with FEV1 (FDR < 0.1). In the replication cohort, these modules were highly preserved and their FEV1 associations were reproducible (P < 0.05). Two of the three modules were negatively related to FEV1 and were enriched in IL8 and IL10 pathways and correlated with neutrophil-specific gene expression. The positively related module, on the other hand, was enriched in DNA transcription and translation and was strongly correlated to CD4+, CD8+ T cell-specific gene expression. Network based approaches are promising tools to identify potential biomarkers for COPD. The ECLIPSE study was funded by GlaxoSmithKline, under ClinicalTrials.gov identifier NCT00292552 and GSK No. SCO104960 The online version of this article (doi:10.1186/s12931-017-0558-1) contains supplementary material, which is available to authorized users.