Identification of Protein Markers for Chronic Ischemic Heart Disease Through Integrated Analysis of the Human Plasma Proteome and Genome-Wide Association Data

BACKGROUND: Chronic ischemic heart disease (CIHD) is characterized by persistent myocardial ischemic due to long-term reduced coronary blood flow. In the past, we mainly relied on surgical intervention or drug therapy to alleviate symptoms, but effective targeted treatments were scarce. Proteomics serves as a key tool to identify novel therapeutic targets. METHODS: This study performed a bidirectional Mendelian randomization (MR) analysis by integrating genome-wide association study (GWAS) data on CIHD (10,894,596 single-nucleotide polymorphisms) with plasma proteomic data encompassing 4907 proteins. We conducted Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to identify pathways linked to candidate protein biomarkers, searched the National Genomics Data Center (NGDC) database for existing evidence of their association with CIHD, and evaluated druggability through multi-dimensional analysis integrating the DSIGDB, ChEMBL, and clinical trial databases. RESULTS: After eliminating the reverse effect, ultimately identifying 28 protein markers, including 16 risk-associated and 12 protective proteins. We also investigated their roles in the pathways related to CIHD. Meanwhile, the search confirmed that five of them were newly discovered protein markers. Ultimately, through evaluation, three priority therapeutic targets (CXCL12, PLAU, CD14) were identified for development. CONCLUSIONS: This study identified some biomarkers related to CIHD and analyzed the possible pathways involved. It also provided some new insights into the identification of the target and druggability.