Therapeutic targets for atherosclerotic coronary artery disease: druggable genome-wide Mendelian randomization analysis.

BACKGROUND AND AIMS: Despite advances in treating atherosclerotic coronary artery disease (ACAD), the risk of major adverse cardiovascular events remains high. We aimed to identify potential therapeutic targets for ACAD by integrating genome-wide association studies (GWAS) and Mendelian randomization (MR) analyses.

METHODS

Leveraging druggable genome data, cis-eQTL/cis-pQTL from blood and coronary artery tissue, alongside GWAS summary data for coronary atherosclerosis, we performed drug-target MR to identify causal genes for ACAD at both transcript and protein levels. Phenome-wide association (PheWAS), protein-protein interaction (PPI) networks, enrichment analysis, molecular docking, and in vivo experiments were also conducted.

RESULTS

MR identified 57 blood cis-eQTL, 50 blood cis-pQTL, and 5 coronary artery cis-eQTL druggable genes potentially causal for coronary atherosclerosis. Notably, CES2 and TGFA showed consistent protective associations in both cis-eQTL and cis-pQTL analyses. Genetically elevated blood CES2 and TGFA levels were significantly associated with reduced ACAD risk (p < 0.001). PheWAS revealed no significant adverse effects for TGFA targeting. PPI and enrichment analyses highlighted metabolic pathways. Ten drugs targeting CES2 and three targeting TGFA were identified; in vivo experiments confirmed that atorvastatin, simvastatin, prasugrel, and vicagrel upregulate circulating CES2, while cetuximab and panitumumab increase circulating TGFA.

CONCLUSIONS

Genetically elevated circulating CES2 and TGFA levels are causally associated with reduced ACAD risk. Several candidate drugs capable of modulating these proteins might offer repurposing opportunities for ACAD prevention, warranting further mechanistic and clinical validation.