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Original article
Gene correlation network analysis to identify regulatory factors in idiopathic pulmonary fibrosis
  1. John E McDonough1,
  2. Naftali Kaminski2,
  3. Bernard Thienpont3,
  4. James C Hogg4,
  5. Bart M Vanaudenaerde1,
  6. Wim A Wuyts1
  1. 1 Laboratory of Respiratory Diseases, Department of Chronic Diseases, Metabolism, and Ageing, KU Leuven, Leuven, Belgium
  2. 2 Section of Pulmonary, Critical Care, and Sleep Medicine, Yale University, New Haven, Connecticut, USA
  3. 3 Laboratory for Functional Epigenetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
  4. 4 Centre for Heart Lung Innovation, St. Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada
  1. Correspondence to Dr John E McDonough, Laboratory of Respiratory Diseases, Department of Chronic Diseases, Metabolism, and Ageing, KU Leuven, Leuven B-3000, Belgium ; john.mcdonough{at}kuleuven.be

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a severe lung disease characterised by extensive pathological changes. The objective for this study was to identify the gene network and regulators underlying disease pathology in IPF and its association with lung function.

Methods Lung Tissue Research Consortium dataset with 262 IPF and control subjects (GSE47460) was randomly divided into two non-overlapping groups for cross-validated differential gene expression analysis. Consensus weighted gene coexpression network analysis identified overlapping coexpressed gene modules between both IPF groups. Modules were correlated with lung function (diffusion capacity, DLCO; forced expiratory volume in 1 s, FEV1; forced vital capacity, FVC) and enrichment analyses used to identify biological function and transcription factors. Module correlation with miRNA data (GSE72967) identified associated regulators. Clinical relevance in IPF was assessed in a peripheral blood gene expression dataset (GSE93606) to identify modules related to survival.

Results Correlation network analysis identified 16 modules in IPF. Upregulated modules were associated with cilia, DNA replication and repair, contractile fibres, B-cell and unfolded protein response, and extracellular matrix. Downregulated modules were associated with blood vessels, T-cell and interferon responses, leucocyte activation and degranulation, surfactant metabolism, and cellular metabolic and catabolic processes. Lung function correlated with nine modules (eight with DLCO, five with FVC). Intermodular network of transcription factors and miRNA showed clustering of fibrosis, immune response and contractile modules. The cilia-associated module was able to predict survival (p=0.0097) in an independent peripheral blood IPF cohort.

Conclusions We identified a correlation gene expression network with associated regulators in IPF that provides novel insight into the pathological process of this disease.

  • idiopathic pulmonary fibrosis

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Footnotes

  • Contributors JEM conceived and performed the study. BT contributed the single cell dataset. NK, JCH, BMV and WW were involved in writing and editing the manuscript.

  • Funding Funded by grants from KULeuven (C24/15/30) and NIH (R01HL127349). JEM was funded by a fellowship from the ERS (RESPIRE2-2015-9192).

  • Competing interests NK is an inventor on a pending patent on use of thyroid hormone as an antifibrotic agent (licensed), as well as a patent on novel biomarkers in IPF (not licensed). NK consulted Biogen Idec, Boehringer Ingelheim, Numedii, MMI, Pliant, Third Rock, Indaloo and Samumed. NK has an ongoing collaboration with MiRagen but no fund exchange.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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