Peripheral blood proteomic profiling of idiopathic pulmonary fibrosis biomarkers in the multicentre IPF-PRO Registry

Jamie L. Todd, Megan L. Neely, Robert Overton, Katey Durham, Mridu Gulati, Howard Huang, Jesse Roman, L. Kristin Newby, Kevin R. Flaherty, Richard Vinisko, Yi Liu, Janine Roy, Ramona Schmid, Benjamin Strobel, Christian Hesslinger, Thomas B. Leonard, Imre Noth, John A. Belperio, Scott M. Palmer, Wael AsiAlbert Baker, Scott Beegle, John A. Belperio, Rany Condos, Francis Cordova, Daniel A. Culver, Joao A.M. De Andrade, Daniel Dilling, Kevin R. Flaherty, Marilyn Glassberg, Mridu Gulati, Kalpalatha Guntupalli, Nishant Gupta, Amy Hajari Case, David Hotchkin, Tristan Huie, Robert Kaner, Hyun Kim, Maryl Kreider, Lisa Lancaster, Joseph Lasky, David Lederer, Doug Lee, Timothy Liesching, Randolph Lipchik, Jason Lobo, Yolanda Mageto, Prema Menon, Lake Morrison, Andrew Namen, Justin Oldham, Rishi Raj, Murali Ramaswamy, Tonya Russell, Paul Sachs, Zeenat Safdar, Barry Sigal, Leann Silhan, Mary Strek, Sally Suliman, Jeremy Tabak, Rajat Walia, Timothy P. Whelan

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which diagnosis and management remain challenging. Defining the circulating proteome in IPF may identify targets for biomarker development. We sought to quantify the circulating proteome in IPF, determine differential protein expression between subjects with IPF and controls, and examine relationships between protein expression and markers of disease severity. Methods: This study involved 300 patients with IPF from the IPF-PRO Registry and 100 participants without known lung disease. Plasma collected at enrolment was analysed using aptamer-based proteomics (1305 proteins). Linear regression was used to determine differential protein expression between participants with IPF and controls and associations between protein expression and disease severity measures (percent predicted values for forced vital capacity [FVC] and diffusion capacity of the lung for carbon monoxide [DLco]; composite physiologic index [CPI]). Multivariable models were fit to select proteins that best distinguished IPF from controls. Results: Five hundred fifty one proteins had significantly different levels between IPF and controls, of which 47 showed a |log2(fold-change)| > 0.585 (i.e. > 1.5-fold difference). Among the proteins with the greatest difference in levels in patients with IPF versus controls were the glycoproteins thrombospondin 1 and von Willebrand factor and immune-related proteins C-C motif chemokine ligand 17 and bactericidal permeability-increasing protein. Multivariable classification modelling identified nine proteins that, when considered together, distinguished IPF versus control status with high accuracy (area under receiver operating curve = 0.99). Among participants with IPF, 14 proteins were significantly associated with FVC % predicted, 23 with DLco % predicted, 14 with CPI. Four proteins (roundabout homolog-2, spondin-1, polymeric immunoglobulin receptor, intercellular adhesion molecule 5) demonstrated the expected relationship across all three disease severity measures. When considered in pathways analyses, proteins associated with the presence or severity of IPF were enriched in pathways involved in platelet and haemostatic responses, vascular or platelet derived growth factor signalling, immune activation, and extracellular matrix organisation. Conclusions: Patients with IPF have a distinct circulating proteome and can be distinguished using a nine-protein profile. Several proteins strongly associate with disease severity. The proteins identified may represent biomarker candidates and implicate pathways for further investigation. Trial registration: ClinicalTrials.gov (NCT01915511).

Original languageEnglish (US)
Article number227
JournalRespiratory Research
Volume20
Issue number1
DOIs
StatePublished - Oct 22 2019

Keywords

  • Interstitial lung diseases
  • Observational study
  • Proteome
  • Registries

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Fingerprint Dive into the research topics of 'Peripheral blood proteomic profiling of idiopathic pulmonary fibrosis biomarkers in the multicentre IPF-PRO Registry'. Together they form a unique fingerprint.

  • Cite this

    Todd, J. L., Neely, M. L., Overton, R., Durham, K., Gulati, M., Huang, H., Roman, J., Newby, L. K., Flaherty, K. R., Vinisko, R., Liu, Y., Roy, J., Schmid, R., Strobel, B., Hesslinger, C., Leonard, T. B., Noth, I., Belperio, J. A., Palmer, S. M., ... Whelan, T. P. (2019). Peripheral blood proteomic profiling of idiopathic pulmonary fibrosis biomarkers in the multicentre IPF-PRO Registry. Respiratory Research, 20(1), [227]. https://doi.org/10.1186/s12931-019-1190-z