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Stratification of asthma phenotypes by airway proteomic signatures

: Schofield, J.P.R.; Burg, D.; Nicholas, B.; Strazzeri, F.; Brandsma, J.; Staykova, D.; Folisi, C.; Bansal, A.T.; Xian, Y.; Guo, Y.; Rowe, A.; Corfield, J.; Wilson, S.; Ward, J.; Lutter, R.; Shaw, D.E.; Bakke, P.S.; Caruso, M.; Dahlen, S.-E.; Fowler, S.J.; Horvath, I.; Howarth, P.; Krug, N.; Montuschi, P.; Sanak, M.; Sandström, T.; Sun, K.; Pandis, I.; Riley, J.; Auffray, C.; Meulder, B. De; Lefaudeux, D.; Sousa, A.R.; Adcock, I.M.; Chung, K.F.; Sterk, P.J.; Skipp, P.J.; Djukanović, R.


The journal of allergy and clinical immunology : JACI 144 (2019), No.1, pp.70-82
ISSN: 0091-6749
ISSN: 1097-6825
ISSN: 1085-8725
Journal Article
Fraunhofer ITEM ()

Background: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment responses and a need for better understanding of the underlying mechanisms. Objective: We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification. Methods: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms. Results: Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 1 0 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms. Conclusion: This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies.