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Identification of transcriptomic markers for developing idiopathic pulmonary fibrosis: an integrative analysis of gene expression profiles.

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) remains a lethal disease with unknown etiology and unmet medical need. The aim of this study was to perform an integrative analysis of multiple public microarray datasets to investigate gene expression patterns between IPF patients and healthy controls. Moreover, functional interpretation of differentially expressed genes (DEGs) was performed to assess the molecular mechanisms underlying IPF progression. DEGs between IPF and normal lung tissues were picked out by GEO2R tool and Venn diagram software. Database for Annotation, Visualization and Integrated Discovery (DAVID) was applied to analyze gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway. Protein-protein interaction (PPI) of these DEGs was visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING). 5520 DEGs were identified in IPF based on six profile datasets, including 3714 up-regulated genes and 1806 down-regulated genes. Using Venn software, a total of 367 commonly altered DEGs were revealed, including 259 up-regulated genes mostly enriched in collagen catabolic process, heparin binding, and the extracellular region. For pathway analysis, up-regulated DEGs were mainly enriched in ECM-receptor interaction, protein digestion and absorption, and focal adhesion. Finally, 24 DEGs with degrees ?10 were screened as hub genes from the PPI network, which were enriched in protein digestion and absorption, ECM-receptor interaction, focal adhesion, PI3K-Akt signaling pathway, amoebiasis, and platelet activation. The present integrative study identified DEGs and hub genes that may be diagnostic biomarkers or therapeutic targets, and provide novel insights into the pathogenesis of IPF.

SUBMITTER: Li D

PROVIDER: S-EPMC7414459 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Identification of transcriptomic markers for developing idiopathic pulmonary fibrosis: an integrative analysis of gene expression profiles.

Li Diandian D Liu Yi Y Wang Bo B

International journal of clinical and experimental pathology 20200701 7

Idiopathic pulmonary fibrosis (IPF) remains a lethal disease with unknown etiology and unmet medical need. The aim of this study was to perform an integrative analysis of multiple public microarray datasets to investigate gene expression patterns between IPF patients and healthy controls. Moreover, functional interpretation of differentially expressed genes (DEGs) was performed to assess the molecular mechanisms underlying IPF progression. DEGs between IPF and normal lung tissues were picked out ...[more]

PMID: 32782692

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Project description:BackgroundIdiopathic Pulmonary Fibrosis (IPF) is one of the most common idiopathic interstitial pneumonia, which can occur all over the world. The median survival time of patients is about 3-5 years, and the mortality is relatively high.ObjectiveTo reveal the potential molecular characteristics of IPF and deepen the understanding of the molecular mechanism of IPF. In order to provide some guidance for the clinical treatment, new drug development, and prognosis judgment of IPF. Although the preliminary conclusion of this study has certain guiding significance for the treatment of IPF and so on, it needs more accurate analytical approaches and large sample clinical trials to verify.Methods220 patients with IPF were divided into different subgroups according to the gene expression profiles, which were obtained from the Gene Expression Omnibus (GEO) database. In addition, these subgroups present different expression forms and clinical features. Therefore, weighted gene coexpression analysis (WGCNA) was used to seek the differences between subtypes. And six subgroup-specific WGCNA modules were identified.ResultsCombined with the characteristics of WGCNA and KEGG enrichment modules, the autophagic pathway was only upregulated in subgroup I and enriched significantly. The differentiation pathways of Th1 and Th2 cells were only upregulated and enriched in subgroup II. At the same time, combined with clinical information, IPF patients in subgroup II were older and more serious, which may be closely related to the differentiation of Th1 and Th2 cells. In contrast, the neuroactive ligand-receptor interaction pathway and Ca+ signaling pathway were significantly upregulated and enriched in subgroup III. Although there was no significant difference in prognosis between subgroup I and subgroup III, their intrinsic biological characteristics were very different. These results suggest that the subtypes may represent risk factors of age and intrinsic biological characteristics and may also partly reflect the severity of the disease.ConclusionIn conclusion, current studies have improved our understanding of IPF-related molecular mechanisms. At the same time, because the results show that patients from different subgroups may have their own unique gene expression patterns, it reminds us that patients in each subgroup should receive more personalized treatment.

Project description:Idiopathic pulmonary fibrosis (IPF) is a type of scarring lung disease characterized by a chronic, progressive, and irreversible decline in lung function. The genetic basis of IPF remains elusive. A transcriptome-wide association study (TWAS) of IPF was performed by FUSION using gene expression weights of three tissues combined with a large-scale genome-wide association study (GWAS) dataset, totally involving 2,668 IPF cases and 8,591 controls. Significant genes identified by TWAS were then subjected to gene ontology (GO) and pathway enrichment analysis. The overlapped GO terms and pathways between enrichment analysis of TWAS significant genes and differentially expressed genes (DEGs) from the genome-wide mRNA expression profiling of IPF were also identified. For TWAS significant genes, protein-protein interaction (PPI) network and clustering modules analyses were further conducted using STRING and Cytoscape. Overall, TWAS identified a group of candidate genes for IPF under the Bonferroni corrected P value threshold (0.05/14929 = 3.35 × 10-6), such as DSP (P TWAS = 1.35 × 10-29 for lung tissue), MUC5B (P TWAS = 1.09 × 10-28 for lung tissue), and TOLLIP (P TWAS = 1.41 × 10-15 for whole blood). Pathway enrichment analysis identified multiple candidate pathways, such as herpes simplex infection (P value = 7.93 × 10-5) and antigen processing and presentation (P value = 6.55 × 10-5). 38 common GO terms and 8 KEGG pathways shared by enrichment analysis of TWAS significant genes and DEGs were identified. In the PPI network, 14 genes (DYNLL1, DYNC1LI1, DYNLL2, HLA-DRB5, HLA-DPB1, HLA-DQB2, HLA-DQA2, HLA-DQB1, HLA-DRB1, POLR2L, CENPP, CENPK, NUP133, and NUP107) were simultaneously detected by hub gene and module analysis. In conclusion, through integrative analysis of TWAS and mRNA expression profiles, we identified multiple novel candidate genes, GO terms and pathways for IPF, which contributes to the understanding of the genetic mechanism of IPF.

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Identification of transcriptomic markers for developing idiopathic pulmonary fibrosis: an integrative analysis of gene expression profiles.

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Identification of transcriptomic markers for developing idiopathic pulmonary fibrosis: an integrative analysis of gene expression profiles.

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