Identification Of Genes Related To Myocardial Infarction Based On Data Integration

Myocardial Infarction(MI)has become one of the major diseases leading to death and disability worldwide.Finding candidate genes for MI can help design gene-targeted drugs and effectively reduce the risk of disease.Genome-Wide Association Studies(GWAS)have found many disease-susceptible sites and regions associated with MI,but GWAS can only identify the association between genetic variation and traits,and distinguishing the most functionally related genes in these loci are still challenging.In this study,several large-scale research data(expression Quantitative Trait Loci(eQTL)summary data,methylation quantitative trait loci(mQTL)summary data,gene expression data and MI GWAS were combined Summary data)to identify potential genetic variants of MI.Based on the Summary-data-based Mendelian Randomization(SMR)method,We have newly identified 4 genes causally related to MI(TMEM116,FES,FURIN,RP11-378J18.8)and verified 2 previously discovered genes(NBEAL1,PHACTR1);7 DNA methylation sites related to MI causality were found(PHACTR1 cg03951877,SH2B3 cg26359133,Cg05469396 of FURIN,cg04510874 and cg06330618 of FES,cg09615821 and cg27076536 of VAC14).We compared the mRNA expression signals of the above six genes in gene expression studies and found that four of them(TMEM116,FES,FURIN,PHACTR1)were differently expressed in MI and control groups(adj.P.Val <0.05).Based on the Weighted Gene Co-expression Network Analysis(WGCNA)method,a co-expression network was constructed on the gene data set consisting of 593 known MI susceptibility genes and TMEM116,FES,and FURIN identified by SMR.It was found that the FURIN gene co-expressed with 7 genes that have been identified as related to MI,including LTA,NFKBIL1,BAT1,PHACTR1,DYDC1,HNRNPM,DENND4 A.Protein-protein interaction(PPI)network analysis found that FES and FURIN interacted with proteins known to be related to MI(JAK1,JAK3,IL4 R,KIT,PIK3R1,MMP14,TGFB1,NOTCH1,NGF and BACE1).Using the plug-in MCODE in the Cytoscape software to construct the MI related module gene PPI sub-network,and dig out the protein function module containing FURIN from the complex protein network,it was found that the PPI sub-network includes a total of 7 genes,namely FURIN,AMAMTS20,ADAMTS4 COCH,OTOF,PCDH15,TMC2.This study provides new evidence of the important role of TMEM116,FES and FURIN in the etiology of MI.FURIN may affect the occurrence of MI through the interaction with known genes,and provide theoretical basis for the subsequent functional studies to clarify the role of TMEM116,FES and FURIN genes in MI pathology.