MRC Centre for Environment and Health & Department of Epidemiology and Biostatistics, Faculty of Medicine, School of Public Health, Imperial College London, United Kingdom.
Data Science Institute, Department of Computing, Imperial College London, United Kingdom; National Heart and Lung Institute, Imperial College London, London, United Kingdom; Royal Brompton and Harefield Hospital, London, United Kingdom.
EBioMedicine. 2024 Jan;99:104936. doi: 10.1016/j.ebiom.2023.104936. Epub 2023 Dec 20.
Eosinophilic and neutrophilic asthma defined by high levels of blood and sputum eosinophils and neutrophils exemplifies the inflammatory heterogeneity of asthma, particularly severe asthma. We analysed the serum and sputum proteome to identify biomarkers jointly associated with these different phenotypes.
Proteomic profiles (N = 1129 proteins) were assayed in sputum (n = 182) and serum (n = 574) from two cohorts (U-BIOPRED and ADEPT) of mild-moderate and severe asthma by SOMAscan. Using least absolute shrinkage and selection operator (LASSO)-penalised logistic regression in a stability selection framework, we sought sparse sets of proteins associated with either eosinophilic or neutrophilic asthma with and without adjustment for established clinical factors including oral corticosteroid use and forced expiratory volume.
We identified 13 serum proteins associated with eosinophilic asthma, including 7 (PAPP-A, TARC/CCL17, ALT/GPT, IgE, CCL28, CO8A1, and IL5-Rα) that were stably selected while adjusting for clinical factors yielding an AUC of 0.84 (95% CI: 0.83-0.84) compared to 0.62 (95% CI: 0.61-0.63) for clinical factors only. Sputum protein analysis selected only PAPP-A (AUC = 0.81 [95% CI: 0.80-0.81]). 12 serum proteins were associated with neutrophilic asthma, of which 5 (MMP-9, EDAR, GIIE/PLA2G2E, IL-1-R4/IL1RL1, and Elafin) complemented clinical factors increasing the AUC from 0.63 (95% CI: 0.58-0.67) for the model with clinical factors only to 0.89 (95% CI: 0.89-0.90). Our model did not select any sputum proteins associated with neutrophilic status.
Targeted serum proteomic profiles are a non-invasive and scalable approach for subtyping of neutrophilic and eosinophilic asthma and for future functional understanding of these phenotypes.
U-BIOPRED has received funding from the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement no. 115010, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013), and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in-kind contributions (www.imi.europa.eu). ADEPT was funded by Johnson & Johnson/Janssen pharmaceutical Company.
通过血液和痰液中嗜酸性粒细胞和中性粒细胞水平高来定义嗜酸性粒细胞和中性粒细胞性哮喘，体现了哮喘，尤其是重度哮喘的炎症异质性。我们分析了血清和痰液的蛋白质组，以确定与这些不同表型共同相关的生物标志物。
通过 SOMAscan 对来自两个队列（U-BIOPRED 和 ADEPT）的轻中度和重度哮喘患者的痰液（n=182）和血清（n=574）中的蛋白质组谱（N=1129 种蛋白质）进行了分析。使用最小绝对收缩和选择算子（LASSO）-惩罚逻辑回归在稳定选择框架中，我们寻求与嗜酸性粒细胞性或中性粒细胞性哮喘相关的稀疏蛋白质集，无论是否调整了包括口服皮质类固醇使用和用力呼气量在内的既定临床因素。
我们确定了 13 种与嗜酸性粒细胞性哮喘相关的血清蛋白，其中 7 种（PAPP-A、TARC/CCL17、ALT/GPT、IgE、CCL28、CO8A1 和 IL5-Rα）在调整了临床因素后被稳定选择，从而获得了 0.84（95%CI：0.83-0.84）的 AUC，而仅使用临床因素的 AUC 为 0.62（95%CI：0.61-0.63）。痰液蛋白分析仅选择了 PAPP-A（AUC=0.81[95%CI：0.80-0.81]）。12 种血清蛋白与中性粒细胞性哮喘相关，其中 5 种（MMP-9、EDAR、GIIE/PLA2G2E、IL-1-R4/IL1RL1 和 Elafin）补充了临床因素，使模型的 AUC 从仅使用临床因素的 0.63（95%CI：0.58-0.67）增加到 0.89（95%CI：0.89-0.90）。我们的模型没有选择任何与中性粒细胞状态相关的痰液蛋白。
靶向血清蛋白质组谱是一种非侵入性和可扩展的方法，可用于对嗜酸性粒细胞和中性粒细胞性哮喘进行亚型分类，并有助于进一步了解这些表型的功能。
U-BIOPRED 已从创新药物倡议（IMI）联合企业获得了第 115010 号联合承诺下的资助，该资助由欧盟第七框架计划（FP7/2007-2013）的资金以及欧洲制药工业和协会联合会（EFPIA）公司的实物贡献组成（www.imi.europa.eu）。ADEPT 由强生/杨森制药公司资助。
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