Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes
Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes
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DOI：
10.1016/j.jaci.2013.12.1091
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发表时间：
2014-04-01
影响因子：
14.2
通讯作者：
Gibson, Peter G.
中科院分区：
文献类型：
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作者：
Baines, Katherine J.;Simpson, Jodie L.;Gibson, Peter G.
背景：呼吸道炎症与哮喘恶化风险、治疗反应和疾病机制有关。目的：本研究旨在识别和验证一个区分哮喘炎症表型的痰基因表达特征。方法：一项哮喘表型生物标志物发现研究从47例哮喘患者的诱导痰中获得了基因表达谱。一项临床验证研究(n=59名哮喘患者)证实了关键基因的差异表达。对6个基因标记进行鉴定和重复性评估(30例哮喘患者和20例对照组)和71例哮喘患者吸入性皮质类固醇(ICS)反应的预测。结果：从277个哮喘炎症表型差异表达基因中，我们鉴定出23个基因在发现人群和验证人群中表现出高度显著的差异表达。6个基因，包括Charcot-Leydon晶体蛋白(CLC)、羧肽酶A3(CPA3)、类脱氧核糖核酸酶I(DNASE1L3)、IL-1β(IL1B)、碱性磷酸酶、组织非特异性同工酶(ALPL)和趋化因子(C-X-C基序)受体2(CXCR2)的特征基因是可复制的，并且可以显著(P12%改变FEV1；AUC，91.5%)。ICS治疗可降低嗜酸粒细胞哮喘患者CLC、CPA3和DNASE1L3的表达。结论：6个生物标志物的痰基因表达特征可重复性和显著区分哮喘的炎症表型，并预测ICS治疗的疗效。这一特征有可能成为一种有用的诊断工具，有助于哮喘的临床诊断和治疗。
Background: Airway inflammation is associated with asthma exacerbation risk, treatment response, and disease mechanisms.Objective: This study aimed to identify and validate a sputum gene expression signature that discriminates asthma inflammatory phenotypes.Methods: An asthma phenotype biomarker discovery study generated gene expression profiles from induced sputum of 47 asthmatic patients. A clinical validation study (n = 59 asthmatic patients) confirmed differential expression of key genes. A 6-gene signature was identified and evaluated for reproducibility (n = 30 asthmatic patients and n = 20 control subjects) and prediction of inhaled corticosteroid (ICS) response (n = 71 asthmatic patients). Receiver operating characteristic curves were calculated, and area under the curve (AUC) values were reported.Results: From 277 differentially expressed genes between asthma inflammatory phenotypes, we identified 23 genes that showed highly significant differential expression in both the discovery and validation populations. A signature of 6 genes, including Charcot-Leydon crystal protein (CLC); carboxypeptidase A3 (CPA3); deoxyribonuclease I-like 3 (DNASE1L3); IL-1 beta (IL1B); alkaline phosphatase, tissue-nonspecific isozyme (ALPL); and chemokine (C-X-C motif) receptor 2 (CXCR2), was reproducible and could significantly (P12% change in FEV1; AUC, 91.5%). ICS treatment reduced the expression of CLC, CPA3, and DNASE1L3 in patients with eosinophilic asthma.Conclusions: A sputum gene expression signature of 6 biomarkers reproducibly and significantly discriminates inflammatory phenotypes of asthma and predicts ICS treatment response. This signature has the potential to become a useful diagnostic tool to assist in the clinical diagnosis and management of asthma.