基于生物信息学分析筛选参与Ig A肾病的关键基因和通路
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摘要
目的利用生物信息学分析筛选IgA肾病相关差异表达基因,旨在深入了解IgA肾病发生机制。方法对基因表达综合数据库(GEO数据库)中的IgA肾病患者和正常对照者的血液(数据编号:GSE73953)和肾脏组织(数据编号:GSE93798)芯片结果进行重新注释和分析,应用Morpheus分别对两个芯片结果进行分析筛选差异表达基因,然后取交集得到共有的差异表达基因。应用DAVID数据库对共有的差异表达基因进行GO和KEGG分析,应用STRING对差异表达基因结果进行蛋白互作分析,应用Cytoscape软件筛选关键基因。结果应用Morpheus分析芯片结果得到184个共有的差异表达基因,GO分析结果提示差异表达基因多在细胞外基质形成、细胞外结构形成、细胞凋亡、细胞程序性死亡等生物过程富集,在细胞外成分、细胞外基质蛋白、细胞外空间等细胞组成富集,在细胞功能调节、酶调节活性、大分子复杂结果等分子功能富集。KEGG分析提示差异表达基因在局部粘连、MAPK等通路富集。蛋白互作分析结果提示前10个关键基因,即PTPRC、FN1、PECAM1、AGTR1、POSTN、AGT、COL4A1、TP53、CYR61、MGAM。Cytoscape的MCODE分析结果提示最显著的差异表达基因主要富集于肾素-血管紧张素系统等通路。结论细胞外基质形成、局部粘连、MAPK等通路可能参与IgA肾病发生发展过程,PTPRC等关键基因及肾素-血管紧张素通路可能是IgA肾病的关键基因/通路,这将为IgA肾病机制的进一步研究提供方向。
Objective To identify the differentially expressed genes and pathways involved in IgA nephropathy using bioinformatics analysis for improving the understanding of the molecule mechanism of IgA nephropathy. Methods The gene expression profiles of GSE73953 and GSE93798 were downloaded from GEO database to make re-annotation and analysis. Morpheus was used to identify the differentially expressed genes and the intersection was taken to identify the common differentially expressed genes. DAVID database was used to make the gene ontology( GO) and Kyoto Encyclopedia of Genes and Genomes Pathway( KEGG) enrichment analysis. Proteinprotein interaction( PPI) network of the differentially expressed genes was performed by STRING and Cytoscape. Results A total of184 differentially expressed genes were identified in IgA nephropathy. GO analysis results showed that these differentially expressed genes were significantly enriched in biological processes( including extracellular matrix organization,extracellular structure organization,regulation of apoptotic process,regulation of programmed cell death,regulation of cell death etc.),cellular component( including extracellular region part,extracellular region,proteinaceous extracellular matrix,extracellular space,extracellular matrix component etc.),and molecular function( including molecular function regulator,enzyme regulator activity,macromolecular complex binding,protein kinase regulator activity,kinase regulator activity etc.). KEGG pathway analysis showed that the differentially expressed genes were enriched in focal adhesion,MAPK signaling pathway etc. The top 10 hub genes,PTPRC,FN1,PECAM1,AGTR1,POSTN,AGT,COL4 A1,TP53,CYR61,MGAM were identified from the PPI network,and sub-networks were involved in significant pathways,including renin-angiotensin system pathway. Conclusion Extracellular matrix formation,local adhesion,MAPK pathway,etc might be involved in the process of IgA nephropathy,and the key genes such as PTPRC and renin-angiotensin system pathway might be the key genes/pathways of IgA nephropathy,which could provide a direction for the further research of mechanism of IgA nephropathy.
Objective To identify the differentially expressed genes and pathways involved in IgA nephropathy using bioinformatics analysis for improving the understanding of the molecule mechanism of IgA nephropathy. Methods The gene expression profiles of GSE73953 and GSE93798 were downloaded from GEO database to make re-annotation and analysis. Morpheus was used to identify the differentially expressed genes and the intersection was taken to identify the common differentially expressed genes. DAVID database was used to make the gene ontology( GO) and Kyoto Encyclopedia of Genes and Genomes Pathway( KEGG) enrichment analysis. Proteinprotein interaction( PPI) network of the differentially expressed genes was performed by STRING and Cytoscape. Results A total of184 differentially expressed genes were identified in IgA nephropathy. GO analysis results showed that these differentially expressed genes were significantly enriched in biological processes( including extracellular matrix organization,extracellular structure organization,regulation of apoptotic process,regulation of programmed cell death,regulation of cell death etc.),cellular component( including extracellular region part,extracellular region,proteinaceous extracellular matrix,extracellular space,extracellular matrix component etc.),and molecular function( including molecular function regulator,enzyme regulator activity,macromolecular complex binding,protein kinase regulator activity,kinase regulator activity etc.). KEGG pathway analysis showed that the differentially expressed genes were enriched in focal adhesion,MAPK signaling pathway etc. The top 10 hub genes,PTPRC,FN1,PECAM1,AGTR1,POSTN,AGT,COL4 A1,TP53,CYR61,MGAM were identified from the PPI network,and sub-networks were involved in significant pathways,including renin-angiotensin system pathway. Conclusion Extracellular matrix formation,local adhesion,MAPK pathway,etc might be involved in the process of IgA nephropathy,and the key genes such as PTPRC and renin-angiotensin system pathway might be the key genes/pathways of IgA nephropathy,which could provide a direction for the further research of mechanism of IgA nephropathy.
引文
[1]Li M,Foo JN,Wang JQ,et al.Identification of new susceptibility loci for Ig A nephropathy in Han Chinese[J].Nat Commun,2015,6:7270.
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[8]王文涛.成人原发性Ig A肾病与血免疫球蛋白及补体的相关关系[J].山西医科大学学报,2018,49(8):87-91.
[9]Malyszko J,Bachorzewska-Gajewska H,Sitniewska E,et al.Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in non-diabetic patients with stage 2-4 chronic kidney disease[J].Ren Fail,2008,30(6):625-628.
[10]Lu Y,Mei Y,Chen L,et al.The role of transcriptional factor D-site-binding protein in circadian CCL2 gene expression in antiThy1 nephritis[J].Cell Mol Immunol,2018:Epub ahead of print.
[11]Crean JK,Furlong F,Finlay D,et al.Connective tissue growth factor[CTGF]/CCN2 stimulates mesangial cell migration through integrated dissolution of focal adhesion complexes and activation of cell polarization[J].FASEB J,2004,18(13):1541-1543.
[12]Abdelsamie SA,Li Y,Huang Y,et al.Oxidized LDL immune complexes stimulate collagenⅣproduction in mesangial cells via Fc gamma receptorsⅠandⅢ[J].Clin Immunol,2011,139(3):258-266.
[13]Kurihara H,Sakai T.Cell biology of mesangial cells:the third cell that maintains the glomerular capillary[J].Anat Sci Int,2017,92(2):173-186.
[14]Lin TJ,Yang SS,Hua KF,et al.SPAK plays a pathogenic role in Ig A nephropathy through the activation of NF-κB/MAPKs signaling pathway[J].Free Radic Biol Med,2016,99:214-224.
[15]Monteiro RC.Recent advances in the physiopathology of Ig A nephropathy[J].Nephrol Ther,2018,14:S1-S8.
[2]Moldoveanu Z,Wyattr,Lee J,et al.Patients with Ig A nephropathy have increased serum galactose-deficient Ig A1 levels[J].Kidney Int,2007,71(11):1148-1154.
[3]Guo Y,Bao Y,Ma M,et al.Identification of key candidate genes and pathways in colorectal cancer by integrated bioinformatical analysis[J].Int J Mol Sci,2017,18(4):E722.
[4]Ashburner M,Ball CA,Blake JA,et al.Gene ontology:tool for the unification of biology[J].Nat Genet,2000,25(1):25.
[5]Kanehisa M,Goto S.KEGG:Kyoto encyclopedia of genes and genomes[J].Nucleic Acids Res,2000,28(1):27-30.
[6]Dennis G,Sherman BT,Hosack DA,et al.DAVID:database for annotation,visualization,and integrated discovery[J].Genome Biol,2003,4(9):R60.
[7]Nan J,Juan L,Gao J,et al.Application value of biochemical and immunological indicators in Lee’s classification of Ig A nephropathy[J].Chin J Lab Med,2016,39(9):695-700.
[8]王文涛.成人原发性Ig A肾病与血免疫球蛋白及补体的相关关系[J].山西医科大学学报,2018,49(8):87-91.
[9]Malyszko J,Bachorzewska-Gajewska H,Sitniewska E,et al.Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in non-diabetic patients with stage 2-4 chronic kidney disease[J].Ren Fail,2008,30(6):625-628.
[10]Lu Y,Mei Y,Chen L,et al.The role of transcriptional factor D-site-binding protein in circadian CCL2 gene expression in antiThy1 nephritis[J].Cell Mol Immunol,2018:Epub ahead of print.
[11]Crean JK,Furlong F,Finlay D,et al.Connective tissue growth factor[CTGF]/CCN2 stimulates mesangial cell migration through integrated dissolution of focal adhesion complexes and activation of cell polarization[J].FASEB J,2004,18(13):1541-1543.
[12]Abdelsamie SA,Li Y,Huang Y,et al.Oxidized LDL immune complexes stimulate collagenⅣproduction in mesangial cells via Fc gamma receptorsⅠandⅢ[J].Clin Immunol,2011,139(3):258-266.
[13]Kurihara H,Sakai T.Cell biology of mesangial cells:the third cell that maintains the glomerular capillary[J].Anat Sci Int,2017,92(2):173-186.
[14]Lin TJ,Yang SS,Hua KF,et al.SPAK plays a pathogenic role in Ig A nephropathy through the activation of NF-κB/MAPKs signaling pathway[J].Free Radic Biol Med,2016,99:214-224.
[15]Monteiro RC.Recent advances in the physiopathology of Ig A nephropathy[J].Nephrol Ther,2018,14:S1-S8.