基于生物信息学探讨合并心力衰竭的扩张型心肌病靶基因的预测

Prediction of Target Genes for Dilated Cardiomyopathy with Heart Failure Based on Bioinformatical Analysis

【目的】为了研究合并心力衰竭的扩张型心肌病发生发展相关的差异基因与调控信号通路,利用生物信息学方法探讨了基因表达汇编(GEO)中的基因芯片和人类基因和遗传疾病的在线目录(OMIM)中扩张型心肌病相关基因。【方法】本研究选择了由德国波鸿大学Herz-&Diabeteszentrum NRW实验室利用临床病例心肌活检标本在GPL570平台进行测序并上传至GEO公共数据库的两张芯片基因集:GSE29819和GSE21610。将合并心力衰竭的扩张型心肌病和正常心脏功能的心肌活检标本分别作为实验组(分别为14例和21例)和对照组(分别为12例和8例)。利用GEO2R对两张芯片中的候选标本以P<0.05为标准进行表达上调差异基因的筛选,并进行京都基因与基因组百科全书(KEGG)通路分析,基因本体(GO)功能分析,及蛋白互作网络(PPI)分析,并通过R语言包中的火山图,Venn图,热图,富集通路气泡图等对结果进行展示,同时用基因集富集分析(GSEA)探索与合并心力衰竭的扩张型心肌病相关的以NOM.P<0.05为标准的KEGG通路及核心基因。以上候选基因分别与OMIM中的已报道过的基因取交集,并结合文献寻找这些候选基因的临床价值。【结果】GEO2R获得共同上调的P<0.05的差异基因173个,主要与炎症信号和细胞增殖分化调控及经典的凋亡信号传导通路相关,与OMIM中754个报道基因相交,得到已报道的表达上调基因3个:用于诊断心力衰竭的NPPA,与细胞因子作用相关的APOA1和调节横向小管重塑的COL6A1。而GSEA分析分别得到来源于NOM.P<0.05的KEGG通路的158个和46个核心基因,再与OMIM中754个报道基因相交,得到核心基因2个:增强心肌收缩力的PRKCA和促进心力衰竭发展的BMP2。【结论】根据生物信息学分析,我们发现筛选出的候选基因PRKCA,BMP2,NPPA,COL6A1很可能与合并心力衰竭的扩张型心肌病的发生发展密切相关,可以为晚期心功能失代偿的扩张型心肌病的治疗提供有意义的研究线索及方向。

【Objective】To study the differentiate expression genes and regulation signaling pathways related to the occurrence and development of dilated cardiomyopathy with heart failure,we used bioinformatics methods to explore gene chip in gene expression omnibus(GEO)and genes related to dilated cardiomyopathy in online mendelian inheritance in man(OMIM).【Methods】GSE21610 and GSE29919 chip gene sets sequenced by Herz-&Diabeteszentrum NRW laboratory of the University of Bochum,Germany with myocardial biopsy specimens from clinical cases under the platform GPL570 and uploaded to GEO public database were selected to perform our study.Myocardial biopsy specimens from dilated cardiomyopathy with heart failure and normal cardiac function were regarded as the experimental group(14 and 21 cases,respectively)and the control group(12 and 8 cases,respectively).Up-regulated expression genes with the criteria:P<0.05,were screened in GEO2R with the selected samples of two chips,which were then used to perform kyoto encyclope?dia of genes and genomes(KEGG)pathways analysis,gene ontology(GO)function analysis,and protein-protein interac?tion(PPI)analysis,and the results were displayed through Volcano map,Venn map,Heat map,and Bubble charts with enrichment pathways drawn by R language packages.Meanwhile,KEGG pathways with the criteria:NOM.P<0.05,and core genes relating to dilated cardiomyopathy with heart failure were performed through gene set enrichment analysis(GSEA).All candidate genes were then intersected with the reported genes in the OMIM,respectively,and clinical significance of these candidate genes was explored in relevant literatures.【Results】A total of 173 up-regulated expression genes with P<0.05,were obtained by GEO2R,which are mainly related to inflammatory signals,cell proliferation and differentiation regulating,and classical apoptotic signaling pathways.These genes were intersected with the 754 reported genes in OMIM,and three reported up-regulated expression genes were obtained:NPPA for diagnosis of heart failure,APOA1 that associates with cytokine action,and COL6A1 that regulates lateral tubular remodeling.158 and 46 core genes from KEGG pathways with NOM.P<0.05 were obtained by GSEA,respectively,which were then intersected with the 754 reported genes in OMIM,and two core genes were obtained:PRKCA,enhancing myocardial contractility,and BMP2,promoting the development of heart failure.【Conclusions】Based on bioinformatics analysis,we found that the candidate genes PRKCA,BMP2,NPPA,and COL6A1 are likely to be closely related to the occurrence and development of dilated cardiomyopathy with heart failure,which can be used to reveal meaningful therapeutic clues and directions for the clinical treatment of dilated cardiomyopathy with advanced cardiac dysfunction.