Stratification of asthma phenotypes by airway proteomic signatures

Abstract

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 10 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.

Needs for Systems Approaches to Better Treat Individuals With Severe Asthma: Predicting Phenotypes and Responses to Treatments

“…Conversely, the neutrophilic proteotype was associated with the upregulation of proteins secreted by neutrophils (azurocidin, S100, annexin A, neutrophil gelatinase-associated lipocalin, myeloperoxidase) (80). Interestingly, in a hypothesis-based approach, Barbaro et al detected the exhaled matrix metalloprotease-9 (MMP9) in different phenotypes of asthma and found it elevated in severe neutrophilic asthma (89), echoing the results of both the aforementioned study by Schofield et al, where MMP9 was associated with neutrophilic inflammation in bronchial mucosa from asthmatic patients (86), and those of a previous study in the field of lung transplantation that showed that the serum MMP9 level was predictive of bronchiolitis obliterans syndrome in lung transplant recipients, a condition also related to airway neutrophilia and bronchial remodeling (90).…”

“…The authors also identified predictive biomarkers associated with the 3 main proteotypes. The eosinophilic proteotype was associated with the upregulation of pro-type-2 immunity proteins mostly via an inhibition of neutrophil activation (transthyretin, serotransferrin, alpha1 anti-trypsin) or via the activation of eosinophils (IgG3, C3, histone H4) (86)(87)(88). Conversely, the neutrophilic proteotype was associated with the upregulation of proteins secreted by neutrophils (azurocidin, S100, annexin A, neutrophil gelatinase-associated lipocalin, myeloperoxidase) (80).…”

Precision Medicine in Childhood Asthma: Omic Studies of Treatment Response

“…Additionally, since the lung microbiome is difficult to sample, the nasal, the salivary, or even the gut microbiome could be examined as non-invasive alternatives to the lung microbiome due to the relationship between the upper and the lower airways [84,85] and the gut-lung axis [72]. Although proteomics and breathomics have been used for profiling of asthma [60,86,87], during the reviewed period, no study has been focused on treatment response in children with asthma. Breathomics and sputum or salivary proteomics could be straightforwardly applicable in the clinics in terms of non-invasiveness, which provides an outstanding benefit in the management of pediatric asthma.…”

The nuts and bolts of omics for the clinical allergist

“…31 Several studies have begun to use proteomics to analyze subtypes of disease, examining nasal secretions from patients with chronic rhinosinusitis, 32,33 as well as sputum samples from subjects with asthma. 34 Overall, however, in relation to allergies and personalized medicine, the field of proteomics is still developing and will likely require further advances in proteomic sequencing technology.…”