Mass spectrometry-based peripheral blood proteomics for biomarker discovery in idiopathic pulmonary fibrosis.

BACKGROUND: The circulating proteome may provide insights into the pathobiology of idiopathic pulmonary fibrosis (IPF) and diagnostic or prognostic biomarkers. We applied liquid chromatography coupled to mass spectrometry to quantify the peripheral blood proteome in patients with IPF and identify proteins associated with disease severity and progression. METHODS: The IPF cohort comprised 299 patients from the IPF-PRO Registry. Controls (n = 99) without known lung disease had similar distributions of age, sex and smoking status to the IPF cohort. Proteins were measured in plasma collected at enrollment using an Evosep One coupled to an Orbitrap Exploris. Data were analyzed with Spectronaut 14 with a deep experimental spectral library and were log2 transformed. Linear regression was used to compare protein abundances in the IPF versus control cohorts and identify proteins associated with disease severity measures at enrollment in the IPF cohort. Cox regression analyses were used to identify proteins associated with outcomes in the IPF cohort, split 75/25 into training and test sets. The false discovery rate was controlled at 5%. RESULTS: Overall, 761 protein groups corresponding to 736 unique genes were detected. Of these, 168 protein groups were significantly different in abundance in the IPF versus control cohorts, of which 39 were ≥ 1.3-fold different. Among the top differentially expressed proteins were surfactant protein B (SFTPB), secretoglobin family 3A member 1, intercellular adhesion molecule 1, thrombospondin 1 and platelet factor 4. In patients with IPF, greater abundance of apolipoprotein A-1 was statistically significantly associated with higher forced vital capacity % predicted at enrollment, while greater abundance of fibulin-1 was statistically significantly associated with lower diffusing capacity of the lungs for carbon monoxide % predicted. Multivariable models selected 4 proteins (SERPINA7, SFTPB, alpha 2 HS glycoprotein, kininogen 1) and 3 clinical factors that best discriminated the risk of respiratory death or lung transplant in patients with IPF, with a C-index of 0.78 in the training set and 0.72 in the test set. CONCLUSIONS: Mass spectrometry-based proteomic analysis of data from the IPF-PRO Registry confirmed proteins previously associated with the presence, severity and progression of IPF and revealed new candidate biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov; No: NCT01915511; registered August 5, 2013; URL: www. CLINICALTRIALS: gov .

Duke Scholars

Author Megan Lee Neely Biostatistics & Bioinformatics, Division of Biostatistics

Author Jamie Lynn Todd Medicine, Pulmonary, Allergy, and Critical Care Medicine