Obeidat Ma'en, Nie Yunlong, Fishbane Nick, Li Xuan, Bossé Yohan, Joubert Philippe, Nickle David C, Hao Ke, Postma Dirkje S, Timens Wim, Sze Marc A, Shannon Casey P, Hollander Zsuzsanna, Ng Raymond T, McManus Bruce, Miller Bruce E, Rennard Stephen, Spira Avrum, Hackett Tillie-Louise, Lam Wan, Lam Stephen, Faner Rosa, Agusti Alvar, Hogg James C, Sin Don D, Paré Peter D
1 The University of British Columbia Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada.
2 Department of Molecular Medicine.
Am J Respir Cell Mol Biol. 2017 Oct;57(4):411-418. doi: 10.1165/rcmb.2016-0284OC.
Chronic obstructive pulmonary disease is the third leading cause of death worldwide. Gene expression profiling across multiple regions of the same lung identified genes significantly related to emphysema. We sought to determine whether the lung and epithelial expression of 127 emphysema-related genes was also related to lung function in independent cohorts, and whether any of these genes could be used as biomarkers in the peripheral blood of patients with chronic obstructive pulmonary disease. To that end, we examined whether the expression levels of these genes were under genetic control in lung tissue (n = 1,111). We then determined whether the mRNA levels of these genes in lung tissue (n = 727), small airway epithelial cells (n = 238), and peripheral blood (n = 620) were significantly related to lung function measurements. The expression of 63 of the 127 genes (50%) was under genetic control in lung tissue. The lung and epithelial mRNA expression of a subset of the emphysema-associated genes, including ASRGL1, LPHN2, and EDNRB, was strongly associated with lung function. In peripheral blood, the expression of 40 genes was significantly associated with lung function. Twenty-nine of these genes (73%) were also associated with lung function in lung tissue, but with the opposite direction of effect for 24 of the 29 genes, including those involved in hypoxia and B cell-related responses. The integrative genomics approach uncovered a significant overlap of emphysema genes associations with lung function between lung and blood with opposite directions between the two. These results support the use of peripheral blood to detect disease biomarkers.
慢性阻塞性肺疾病是全球第三大致死原因。对同一肺部多个区域进行基因表达谱分析，确定了与肺气肿显著相关的基因。我们试图确定127个与肺气肿相关基因在肺部和上皮细胞中的表达是否也与独立队列中的肺功能相关，以及这些基因中是否有任何一个可作为慢性阻塞性肺疾病患者外周血中的生物标志物。为此，我们检查了这些基因在肺组织（n = 1111）中的表达水平是否受遗传控制。然后，我们确定这些基因在肺组织（n = 727）、小气道上皮细胞（n = 238）和外周血（n = 620）中的mRNA水平是否与肺功能测量值显著相关。127个基因中的63个（50%）在肺组织中的表达受遗传控制。包括ASRGL1、LPHN2和EDNRB在内的一部分与肺气肿相关基因在肺部和上皮细胞中的mRNA表达与肺功能密切相关。在外周血中，40个基因的表达与肺功能显著相关。其中29个基因（73%）在肺组织中也与肺功能相关，但29个基因中有24个基因的作用方向相反，包括那些参与缺氧和B细胞相关反应的基因。综合基因组学方法揭示了肺气肿基因与肺功能之间在肺和血液中的关联存在显著重叠，且两者方向相反。这些结果支持使用外周血来检测疾病生物标志物。
