Causal Association Between 4907 Circulating Proteins and Ischaemic Cardiomyopathy:A Two-Sample Mendelian Randomisation Study Based on the European Population
Objective Ischaemic cardiomyopathy is a common cardiovascular disease that occurs in all age groups.It mainly affects middle-aged and the elderly individuals,and poses a serious threat to human health.A prolonged ischemia will lead to cell necrosis and apoptosis,and even fibrous tissue proliferation,and can easily induce severe arrhythmias and myocardial infarction.Circulating proteins,constituting the plasma protein fraction,are key regulators of diverse biological activities.So exploring the causal association between cir-culating proteins and ischemic cardiomyopathy can help screening drug targets.Methods Instrumental variables were derived from the Finnish Biobank and a genome-wide association study database encompassing 4907 circulating proteins.Five robust Mendelian randomi-zation(MR)analysis methods were used to determine the causal association between exposure and outcome,including the inverse vari-ance weighted(IVW)method,MR-Egger regression,weighted median,simple model,and weighted model.When the above analysis methods yielded disparate conclusions,the IVW method was given precedence.Sensitivity analyses included Mendelian randomized multi-ple validity and outlier global tests,Cochran's Q test,MR-Egger intercept test,and leave-one-out sensitivity analysis.Meanwhile,false discovery rate(FDR)correction was applied to the outcomes of all IVW methods to identify the most relevant circulating proteins to ischaemic cardiomyopathy.Gene Ontology database and the Kyoto Encyclopedia of Genes and Genomes were used to apply the enrichment analysis on the positive protine.and to screen the disease-related pathways.Results A total of 2 circulating proteins were identified negatively associated with ischaemic cardiomyopathy in this study:vacuolar protein sorting 29[PIVW＜0.001,PFDR=0.049,OR(odds ratio)=0.866,95％CI(confidence interval):0.820-0.916];baculovirus IAP repeat inclusion protein 2(PIVW＜0.001,PFDR＜0.001,OR=0.834,95％CI:0.783-0.888).A series of pathways associated with ischaemic cardiomyopathy were identified through enrichment analysis:regulation of protein K63-linked ubiquitination,negative regulation of necrotic processes,reverse transcription com-plexes,NF-κB signaling pathway,and Hippo signaling pathway.Conclusion The MR analysis we used can identify 2 circulating pro-teins associated with ischaemic cardiomyopathy.The interference of confounding factors can be avoided for the large scale of sample size.This study provides a significant guidance for clinical treatment.
万方数据
维普
