A Severe Asthma Disease Signature from Gene Expression Profiling of Peripheral Blood from U-BIOPRED Cohorts
A Severe Asthma Disease Signature from Gene Expression Profiling of Peripheral Blood from U-BIOPRED Cohorts
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DOI：
10.1164/rccm.201604-0866oc
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发表时间：
2017-05-15
影响因子：
24.7
通讯作者：
Djukanovic, Ratko
中科院分区：
文献类型：
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作者：
Bigler, Jeannette;Boedigheimer, Michael;Djukanovic, Ratko
基本原理：在分子水平上对哮喘进行分层，特别是使用可获得的生物标本，可以极大地使患者选择靶向治疗成为可能。目的：确定血液分析的价值，以确定临床定义的哮喘和非哮喘组之间的转录差异，根据基因表达确定潜在的患者亚组，并探索与确定的差异相关的生物学途径。通过微阵列分析来自U-BIOPRED（预测呼吸系统疾病结局的无偏生物标志物）研究中的610名哮喘患者和对照参与者的血液，生成转录组学图谱。差异表达基因（DEG）通过方差分析进行鉴定，包括RNA质量、性别和临床部位的协变量，并应用免疫途径分析。通过分层聚类和拓扑数据分析创建基于DEG的患者亚组。测量和主要结果：重度哮喘患者和非哮喘参与者之间共有1，693个基因差异表达。在不吸烟的重度哮喘和轻度/中度哮喘亚组中，与非哮喘受试者的差异显著相关（r = 0.76），重度哮喘组的效应量更大。大多数（但不是全部）差异可由循环免疫细胞群的差异解释。通路分析显示，在严重哮喘患者中，趋化性、迁移和髓样细胞运输增加，B淋巴细胞发育和造血祖细胞减少，淋巴器官发育不全。DEG的聚类分析导致在对口服皮质类固醇的分子反应不同的严重哮喘患者中建立亚组。临床定义的哮喘患者亚组和非哮喘个体之间以及通过转录谱定义的严重哮喘患者亚组之间的血液基因表达差异，显示了血液分析在对哮喘患者进行分层和识别分子通路以进行进一步研究方面的价值。
Rationale: Stratification of asthma at the molecular level, especially using accessible biospecimens, could greatly enable patient selection for targeted therapy.Objectives: To determine the value of blood analysis to identify transcriptional differences between clinically defined asthma and nonasthma groups, identify potential patient subgroups based on gene expression, and explore biological pathways associated with identified differences.Methods: Transcriptomic profiles were generated by microarray analysis of blood from 610 patients with asthma and control participants in the U-BIOPRED (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes) study. Differentially expressed genes (DEGs) were identified by analysis of variance, including covariates for RNA quality, sex, and clinical site, and Ingenuity Pathway Analysis was applied. Patient subgroups based on DEGs were created by hierarchical clustering and topological data analysis.Measurements and Main Results: A total of 1,693 genes were differentially expressed between patients with severe asthma and participants without asthma. The differences from participants without asthma in the nonsmoking severe asthma and mild/moderate asthma subgroups were significantly related (r = 0.76), with a larger effect size in the severe asthma group. The majority of, but not all, differences were explained by differences in circulating immune cell populations. Pathway analysis showed an increase in chemotaxis, migration, and myeloid cell trafficking in patients with severe asthma, decreased B-lymphocyte development and hematopoietic progenitor cells, and lymphoid organ hypoplasia. Cluster analysis of DEGs led to the creation of subgroups among the patients with severe asthma who differed in molecular responses to oral corticosteroids.Conclusions: Blood gene expression differences between clinically defined subgroups of patients with asthma and individuals without asthma, as well as subgroups of patients with severe asthma defined by transcript profiles, show the value of blood analysis in stratifying patients with asthma and identifying molecular pathways for further study.