Channing Division of Network Medicine, Dept of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Division of Pulmonary and Critical Care Medicine, Dept of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Eur Respir J. 2022 May 19;59(5). doi: 10.1183/13993003.00569-2021. Print 2022 May.
The molecular basis of airway remodelling in chronic obstructive pulmonary disease (COPD) remains poorly understood. We identified gene expression signatures associated with chest computed tomography (CT) scan airway measures to understand molecular pathways associated with airway disease.
In 2396 subjects in the COPDGene Study, we examined the relationship between quantitative CT airway phenotypes and blood transcriptomes to identify airway disease-specific genes and to define an airway wall thickness (AWT) gene set score. Multivariable regression analyses were performed to identify associations of the AWT score with clinical phenotypes, bronchial gene expression and genetic variants.
Type 1 interferon (IFN)-induced genes were consistently associated with AWT, square root wall area of a hypothetical airway with 10 mm internal perimeter (Pi10) and wall area percentage, with the strongest enrichment in AWT. A score derived from 18 genes whose expression was associated with AWT was associated with COPD-related phenotypes including reduced lung function (forced expiratory volume in 1 s percentage predicted β= -3.4; p<0.05) and increased exacerbations (incidence rate ratio 1.7; p<0.05). The AWT score was reproducibly associated with AWT in bronchial samples from 23 subjects (β=3.22; p<0.05). The blood AWT score was associated with genetic variant rs876039, an expression quantitative trait locus for , a gene that regulates IFN signalling and is associated with inflammatory diseases.
A gene expression signature with IFN-stimulated genes from peripheral blood and bronchial brushings is associated with CT AWT, lung function and exacerbations. Shared genes and genetic associations suggest viral responses and/or autoimmune dysregulation as potential underlying mechanisms of airway disease in COPD.
慢性阻塞性肺疾病（COPD）气道重塑的分子基础仍知之甚少。我们确定了与胸部计算机断层扫描（CT）气道测量相关的基因表达特征，以了解与气道疾病相关的分子途径。
在 COPDGene 研究的 2396 名受试者中，我们研究了定量 CT 气道表型与血液转录组之间的关系，以确定气道疾病特异性基因，并定义气道壁厚度（AWT）基因集评分。进行多变量回归分析以确定 AWT 评分与临床表型、支气管基因表达和遗传变异的关联。
1 型干扰素（IFN）诱导基因与 AWT、假想气道的平方根壁面积（Pi10）和壁面积百分比始终相关，其中 AWT 的富集最强。与 AWT 相关的 18 个基因表达衍生的评分与 COPD 相关表型相关，包括肺功能下降（1 秒用力呼气量占预计值的百分比 β= -3.4；p<0.05）和发作增加（发病率比 1.7；p<0.05）。在 23 名受试者的支气管样本中，AWT 评分与 AWT 具有可重复性相关性（β=3.22；p<0.05）。血液 AWT 评分与基因变异 rs876039 相关，rs876039 是 的表达数量性状基因座，该基因调节 IFN 信号并与炎症性疾病相关。
来自外周血和支气管刷取物的 IFN 刺激基因的基因表达特征与 CT AWT、肺功能和发作相关。共同的基因和遗传关联表明病毒反应和/或自身免疫失调可能是 COPD 气道疾病的潜在机制。
