Journal Article

Gene correlation network analysis to identify regulatory factors in idiopathic pulmonary fibrosis

Hogg, James C, Kaminski, Naftali, Thienpont, Bernard, Wuyts, Wim A, McDonough, John E, Vanaudenaerde, Bart M

2019

Overview

BackgroundIdiopathic 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.MethodsLung 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.ResultsCorrelation 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.ConclusionsWe identified a correlation gene expression network with associated regulators in IPF that provides novel insight into the pathological process of this disease.

• Publisher: BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Aged / Cancer / Clustering / Datasets / Female / Gene expression / Gene Regulatory Networks - genetics / Genetic Predisposition to Disease / Humans / Idiopathic Pulmonary Fibrosis - genetics / Idiopathic Pulmonary Fibrosis - mortality / Idiopathic Pulmonary Fibrosis - physiopathology / Interstitial Lung Disease / Lung - physiopathology / Lung diseases / Male / Middle Aged / Principal components analysis / Pulmonary fibrosis / Reproducibility of Results / Respiratory Function Tests - methods / Studies / Surfactants / Survival Analysis / Thoracic surgery / Transcription factors / Transcriptome - genetics