Integrated Bioinformatics Analysis Identifies Phenotype-associated Biomarkersin Patients With Dilated Cardiomyopathy

Objective: Dilated cardiomyopathy is a heart disease characterized by progressive cardiacdilationand reduced myocardial contractility.In general,patients with dilated cardiomyopathy have a higher mortality rate when they develop symptoms of heart failure.Dilated cardiomyopathy is closely related to genetic factors.This study will analyze the whole gene changes in the myocardial tissue of dilated cardiomyopathy and explore the potential biomarkers and therapeutic targets of this disease through bioinformatics methods.Method: Three gene expression profiles(GSE3585,GSE42955 and GSE9800)containing gene expression data of cardiac tissue samples from dilated cardiomyopathywere downloaded from the Gene Expression Omnibus(GEO)database.Differentially expressed genes(DEGs)were screened after the standardization of the original data preprocessing.Gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysiswere performed to analyze DEGs.The DEGs were imported into the STRING website for protein-protein interaction(PPI)network analysis,and 20 top core genes with the most intensive connections were selected from the protein interaction network for visualization through Cytoscape software.In addition,the GSE17800 profiles containing clinical information of patients with dilated cardiomyopathy was downloaded.The correlation between 20 core genes and left ventricular ejection fraction(LVEF)was analyzedto explore genes associated with LVEF.Gene expression data and clinical information of GSE17800 were used to verify whether there were differences in expression of genes related to LVEF.ROC curve was used to evaluate the diagnostic efficacy of DEGswhich were related to cardiac function in dilated cardiomyopathy.Result: Thedata files of GSE3585,GSE42955 and GSE9800 contained the expression profiles of 31 dilated cardiomyopathy tissue samples and 12 normal myocardial tissue samples.The GSE17800 data file contained myocardial tissue from 40 patients with dilated cardiomyopathy and 8 normal patients.Our results showed that 68 differentially expressed genes,of which 41 up-regulated genes and down-regulated 27 genes in the myocardial tissue of dilated cardiomyopathy were screened from the three data files(GSE3585,GSE42955 and GSE9800).The GO analysis results showed that the DEGs of dilated cardiomyopathy were enriched in cardiac contraction and regulation,myocardial hypertrophy,inflammatory response,extracellular matrix,extracellular matrix protein,and cellular exosomes.Analysis of the KEGG signaling pathway showed that these differentially expressed genes were associated with signaling pathways such as malaria and influenza virus A.The PPI network was constructed based on DEGs to screen out the 20 core genes of connectivity score in the interaction network,including up-regulated genes for CTGF,COL1A1,COL1A2,LUM,ONG,FOMD,ASPN,OMD,ANKRD1,DPT,JAK2,NPPB,NPPA,and down-regulated genes for STAT4,STAT3,CCL2,ICM1,MYH6,C3,and SELE.The results of correlation analysis showed that NPPA,NPPB,ASPN,COL1A2 and CTGF were closely related to the LVEF in patients wtih dilated cardiomyopathy.The results of differential gene expression analysis in the GSE17800 showed that NPPA,NPPB,ASPN,COL1A2 and CTGF were all increased in the cardiac tissue of dilated cardiomyopathy compared with non-failing cardiac tissue.ROC curve suggested that NPPA,NPPB,ASPN,COL1A2 and CTGF had a diagnostic value for dilated cardiomyopathyConclusion: We firstly demonstrate that DEGs in dilated cardiomyopathy were closely related to inflammatory response,cell growth regulation,extracellular matrix proteins,and malaria using bioinformatics methods.Our study showed that ASPN,NPPA,NPPB,COL1A2,and CTGF were increasing in DCM;Forthemore,they have a negative correlated with LVEF in patients with dilated cardiomyopathy.As a secreted protein of extracellular matrix,ASPN may mediate the pathological process of dilated cardiomyopathy through the fibrosis of extracellular matrix,and become a potential biomarker and a new therapeutic target for dilated cardiomyopathy.