Study On Identification Of Important Biomarkers And Biological Characteristics Related To Complex Diseases Based On Microarray Expression Profiles

Complex diseases generally refer to diseases caused by the interaction of multiple genetic variations and environmental factors,such as cancer,atrial fibrillation,diabetes and hypertension,etc.So far,the pathogenesis of many complex diseases is still unclear.Therefore,the identification of important biomarkers and molecular biological characteristics related to complex diseases is conducive to understand the mechanism of occurrence and development of diseases,and can provide help for the diagnosis,treatment and prognosis of diseases.Gastric cancer?GC?is a malignant tumor of digestive system with high morbidity and mortality,while atrial fibrillation?AF?is one of the most common arrhythmias that increase the risk of cardiovascular complications.Cancer and AF share risk factors.Two diseases can interact with each other and increase the risk of another disease if they coexist.Therefore,based on microarray expression profiles,the bioinformatics methods and tools were used to identify the important biomarkers and molecular biological characteristics associated with GC and AF,respectively.Then,the molecular biological characteristics of two complex diseases were compared.It provides a theoretical and technical basis for understanding the pathological relationship between GC and AF at the molecular level.The main contents are as follows:?1?Based on the transcriptional expression profiles with only disease samples,the important mRNA biomarkers and molecular biological characteristics in molecular subtypes of GC were calculated and identified.Firstly,a genome-wide co-expression network was constructed according to the mRNA expression profiles of three GC subtypes?invasive,proliferative and metabolic?,respectively.Secondly,the hierarchical clustering was used to divide the genome-wide co-expression network into the functional modules that were named as subnetworks in this thesis.Then,the key mRNA sets related to subtypes were screened from subnetwork,and the gene ontology and pathway enrichment analysis of key mRNAs in each subtype was performed.Finally,through the comparison and analysis of the key mRNA sets and the enriched functions among the three subtypes,the common and specific biomarkers and molecular biological characteristics among the subtypes were obtained.207 mRNAs were identified as the key mRNAs of invasive,215 mRNAs for the proliferative and 204 mRNAs for the metabolic subtypes.By the comparative analysis,there was no common key mRNAs among the three subtypes and there were fewer key mRNAs between each pair of three subtypes.Therefore,most of key mRNAs screened were unique for each subtype.ARHGAP15?CAP2?COL14A1?DARC?FERMT2?FHL1?FLNA?RAB23?SMYD1?SPON1?ZEB1 are specific mRNAs in the invasive and BUB1B?KIF11?KIF18B?NUSAP1?SYNPO2 are specific mRNAs in the proliferative.It is possible that the specific mRNAs in each subtype cause differences between them.They have the potential to be specific targeted biomarkers for each subtype.The results also showed that the invasive and the proliferative shared cytoskeleton organization,microtubule cytoskeleton organization,cytoskeleton,spindle and structural molecule activity.The invasive and the metabolic shared positive regulation of molecular function.The proliferative and the metabolic shared cell cycle phase,cell cycle process,cell division and mitotic cell cycle.It indicates that there are some same molecular biological characteristics between each pair of three subtypes.However,three subtypes did not share the same molecular biological characteristics and the molecular biological characteristics among three subtypes are distinct.This study may be useful for personalized diagnosis and treatment,and screening for molecular targeted drugs of different subtypes in GC.?2?Based on the constructed lncRNA and mRNA transcriptional expression profiles,the important lncRNA biomarkers and molecular biological characteristics in valvular heart disease with atrial fibrillation?AF-VHD?were calculated and identified.Firstly,the t test and fold change were used to screen the differentially expressed?DE?lncRNAs and mRNAs.Secondly,lncRNA subgroups were identified according to positional relationships between DE lncRNAs and DE mRNAs in the genome.Thirdly,the interaction network among DE lncRNAs,DE mRNAs and transcription factors?TFs?was constructed according to the co-expression relationship between DE lncRNAs and DE mRNAs and the regulatory relationship between DE mRNAs and TFs.The lncRNA associated triplets?denoted by LncATs?were identified from the network.Fourthly,whether the nearby mRNAs of lncRNAs and mRNAs in LncATs interact with the drugs associated with AF or other cardiac arrhythmias were investigated.Finally,the gene ontology and pathway enrichment analyses of DE mRNAs were performed to identify molecular biological characteristics of AF-VHD.Based on the lncRNA and mRNA transcriptional expression profiles,620 DE lncRNAs?262 up-regulated and 358 down-regulated lncRNAs?and 452 DE mRNAs?169 up-regulated and 283 down-regulated mRNAs?were identified.Three subgroups of lncRNAs were mined from the identified DE lncRNAs: antisense lncRNAs,enhancer lncRNAs and lincRNAs.TCONS₀0008697 and TCONS₀0026702 were possibly associated with the development of AF-VHD by acting on PDLIM3 and DTNA,respectively.665 LncATs were identified from the interaction network among DE lncRNAs,DE mRNAs and TFs.TCONS₀0013502,ENST00000505997,uc002 upi.4,ENST00000577545 and ENST00000527314 may affect AF-VHD with c-Rel for binding GJA5.TCONS₀0010459,ENST00000506593,TCONS₀0019593,ENST00000441971,ENST00000554926,TCONS₀0001640 and TCONS₀0016111 may affect AF-VHD with HNF-3beta for binding MYOZ1.Those lncRNAs and TFs related to VIP,PDE1 B and LYZ may affect AF by acting on these mRNAs according to interactions between drug and mRNAs.The results also showed that AF-VHD were mainly related to positive regulation of T-cell migration,myofibril,potassium ion transmembrane transporter activity,oxygen transport,arrhythmogenic right ventricular cardiomyopathy and adrenergic signaling in cardiomyocytes.The myofibril,contractile fiber,hydrolase activity and potassium ion transmembrane transporter activity,and arrhythmogenic right ventricular cardiomyopathy and cholinergic synapse pathways are associated with AF.This study provides a theoretical basis and a new perspective for understanding the molecular mechanism of AF-VHD.?3?Based on mRNA transcriptional expression profiles,the important biomarkers and molecular biological characteristics between GC and AF were identified and compared.Firstly,DE mRNAs associated with each disease were identified by t test and fold change,respectively.Then,the protein-protein interaction networks related to each disease were predicted on the STRING database using DE mRNAs.The potential important biomarkers for each disease were mined by analyzing the characteristics of each protein-protein interaction network.Next,the molecular biological characteristics related to each disease were analyzed by gene ontology and pathway enrichment analyses of DE mRNAs,respectively.Finally,the similarities and differences of the important biomarkers and molecular biological characteristics between GC and AF were illustrated.Although the same important biomarkers between both diseases did not been found,the expression levels of CXCR2,which is an important targeting molecule associated with AF were significantly different between two diseases.It has been reported that the interaction between CXCR2 and CXCR4 can promote the migration and invasion of GC,and CXCR4 was associated with atrial remodeling.Thus,CXCR2 may influence AF through the interaction with CXCR4.The results also showed that both diseases had some of the same molecular biological characteristics,such as chemotaxis,immune response,epithelial cell differentiation,positive regulation of neutrophil chemotaxis,extracellular space and extracellular exosome,in which the chemotaxis and immune responses have been reported to be related to the occurrence and development of GC and AF in literatures.This study provides a theoretical and technical basis for future studies on the mechanisms of gastric cancer with atrial fibrillation or atrial fibrillation with gastric cancer.