Modena Brian D, Bleecker Eugene R, Busse William W, Erzurum Serpil C, Gaston Benjamin M, Jarjour Nizar N, Meyers Deborah A, Milosevic Jadranka, Tedrow John R, Wu Wei, Kaminski Naftali, Wenzel Sally E
1 Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Asthma Institute at UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
2 Scripps Translational Science Institute, The Scripps Research Institute, La Jolla, California.
Am J Respir Crit Care Med. 2017 Jun 1;195(11):1449-1463. doi: 10.1164/rccm.201607-1407OC.
Severe asthma (SA) is a heterogeneous disease with multiple molecular mechanisms. Gene expression studies of bronchial epithelial cells in individuals with asthma have provided biological insight and underscored possible mechanistic differences between individuals.
Identify networks of genes reflective of underlying biological processes that define SA.
Airway epithelial cell gene expression from 155 subjects with asthma and healthy control subjects in the Severe Asthma Research Program was analyzed by weighted gene coexpression network analysis to identify gene networks and profiles associated with SA and its specific characteristics (i.e., pulmonary function tests, quality of life scores, urgent healthcare use, and steroid use), which potentially identified underlying biological processes. A linear model analysis confirmed these findings while adjusting for potential confounders.
Weighted gene coexpression network analysis constructed 64 gene network modules, including modules corresponding to T1 and T2 inflammation, neuronal function, cilia, epithelial growth, and repair mechanisms. Although no network selectively identified SA, genes in modules linked to epithelial growth and repair and neuronal function were markedly decreased in SA. Several hub genes of the epithelial growth and repair module were found located at the 17q12-21 locus, near a well-known asthma susceptibility locus. T2 genes increased with severity in those treated with corticosteroids but were also elevated in untreated, mild-to-moderate disease compared with healthy control subjects. T1 inflammation, especially when associated with increased T2 gene expression, was elevated in a subgroup of younger patients with SA.
In this hypothesis-generating analysis, gene expression networks in relation to asthma severity provided potentially new insight into biological mechanisms associated with the development of SA and its phenotypes.
重度哮喘（SA）是一种具有多种分子机制的异质性疾病。对哮喘患者支气管上皮细胞的基因表达研究提供了生物学见解，并强调了个体间可能存在的机制差异。
识别反映定义SA的潜在生物学过程的基因网络。
通过加权基因共表达网络分析，对重度哮喘研究项目中155例哮喘患者和健康对照者的气道上皮细胞基因表达进行分析，以识别与SA及其特定特征（即肺功能测试、生活质量评分、紧急医疗使用和类固醇使用）相关的基因网络和图谱，这可能揭示潜在的生物学过程。线性模型分析在调整潜在混杂因素的同时证实了这些发现。
加权基因共表达网络分析构建了64个基因网络模块，包括与T1和T2炎症、神经元功能、纤毛、上皮生长和修复机制相对应的模块。虽然没有网络能选择性地识别SA，但与上皮生长、修复和神经元功能相关模块中的基因在SA中明显减少。上皮生长和修复模块的几个枢纽基因位于17q12 - 21位点，靠近一个著名的哮喘易感位点。在接受皮质类固醇治疗的患者中，T2基因随病情严重程度增加，但与健康对照相比，在未经治疗的轻至中度疾病中也升高。在一组年轻的SA患者亚组中，T1炎症，特别是与T2基因表达增加相关时，有所升高。
在这项产生假设的分析中，与哮喘严重程度相关的基因表达网络为与SA及其表型发展相关的生物学机制提供了潜在的新见解。
