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Respiratory Research
Published in: Respiratory Research 1/2023

Open Access 01-12-2023 | Idiopathic Pulmonary Fibrosis | Research

Integrative multi-omics analysis reveals novel idiopathic pulmonary fibrosis endotypes associated with disease progression

Authors: Peifeng Ruan, Jamie L Todd, Hongyu Zhao, Yi Liu, Richard Vinisko, Julia F. Soellner, Ramona Schmid, Robert J. Kaner, Tracy R. Luckhardt, Megan L. Neely, Imre Noth, Mary Porteous, Rishi Raj, Zeenat Safdar, Mary E Strek, Christian Hesslinger, Scott M. Palmer, Thomas B. Leonard, Margaret L. Salisbury

Published in: Respiratory Research | Issue 1/2023

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Abstract

Background

Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix in the pulmonary interstitium and progressive functional decline. We hypothesized that integration of multi-omics data would identify clinically meaningful molecular endotypes of IPF.

Methods

The IPF-PRO Registry is a prospective registry of patients with IPF. Proteomic and transcriptomic (including total RNA [toRNA] and microRNA [miRNA]) analyses were performed using blood collected at enrollment. Molecular data were integrated using Similarity Network Fusion, followed by unsupervised spectral clustering to identify molecular subtypes. Cox proportional hazards models tested the relationship between these subtypes and progression-free and transplant-free survival. The molecular subtypes were compared to risk groups based on a previously described 52-gene (toRNA expression) signature. Biological characteristics of the molecular subtypes were evaluated via linear regression differential expression and canonical pathways (Ingenuity Pathway Analysis [IPA]) over-representation analyses.

Results

Among 232 subjects, two molecular subtypes were identified. Subtype 1 (n = 105, 45.3%) and Subtype 2 (n = 127, 54.7%) had similar distributions of age (70.1 +/- 8.1 vs. 69.3 +/- 7.6 years; p = 0.31) and sex (79.1% vs. 70.1% males, p = 0.16). Subtype 1 had more severe disease based on composite physiologic index (CPI) (55.8 vs. 51.2; p = 0.002). After adjusting for CPI and antifibrotic treatment at enrollment, subtype 1 experienced shorter progression-free survival (HR 1.79, 95% CI 1.28,2.56; p = 0.0008) and similar transplant-free survival (HR 1.30, 95% CI 0.87,1.96; p = 0.20) as subtype 2. There was little agreement in the distribution of subjects to the molecular subtypes and the risk groups based on 52-gene signature (kappa = 0.04, 95% CI= -0.08, 0.17), and the 52-gene signature risk groups were associated with differences in transplant-free but not progression-free survival. Based on heatmaps and differential expression analyses, proteins and miRNAs (but not toRNA) contributed to classification of subjects to the molecular subtypes. The IPA showed enrichment in pulmonary fibrosis-relevant pathways, including mTOR, VEGF, PDGF, and B-cell receptor signaling.

Conclusions

Integration of transcriptomic and proteomic data from blood enabled identification of clinically meaningful molecular endotypes of IPF. If validated, these endotypes could facilitate identification of individuals likely to experience disease progression and enrichment of clinical trials.

Trial registration

NCT01915511
Appendix
Available only for authorised users
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Metadata
Title
Integrative multi-omics analysis reveals novel idiopathic pulmonary fibrosis endotypes associated with disease progression
Authors
Peifeng Ruan
Jamie L Todd
Hongyu Zhao
Yi Liu
Richard Vinisko
Julia F. Soellner
Ramona Schmid
Robert J. Kaner
Tracy R. Luckhardt
Megan L. Neely
Imre Noth
Mary Porteous
Rishi Raj
Zeenat Safdar
Mary E Strek
Christian Hesslinger
Scott M. Palmer
Thomas B. Leonard
Margaret L. Salisbury
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2023
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-023-02435-0

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