Identification of potential drug targets for coronary atherosclerosis from genetic insights: A Mendelian randomization study

Coronary atherosclerosis (CA) is a chronic cardiovascular disease characterized by the accumulation of lipid plaques in coronary arteries, leading to vascular narrowing and impaired myocardial blood supply, which can result in severe complications, such as angina and myocardial infarction, and may even be life-threatening. Despite advancements in CA treatment, including medication and surgery, the complex mechanisms of plaque formation result in some patients responding poorly to existing therapies, and specific targets for precision treatment remain unclear. The present study utilized Mendelian randomization (MR) to investigate therapeutic targets for CA. Cis-expression quantitative trait loci (cis-eQTL, exposure data) were obtained from the eQTLGen consortium, which includes a sample of 31,684 individuals. Summary statistics for CA (outcome data) were obtained from the largest CA genome-wide association studies dataset, covering 456,348 individuals (including 16,041 cases and 440,307 controls), supplemented with data from the UK Biobank and FinnGen studies for external validation. Colocalization analysis was employed to examine whether CA risk and gene expression were driven by a shared single nucleotide polymorphism, thereby determining colocalized signals. Subsequently, drug prediction and molecular docking analysis were conducted to validate the druggability and pharmacological potential of the target genes, identifying promising therapeutic targets. The MR analysis identified nine drug targets, four of which were supported by colocalization, providing further evidence of their significance. Phenome-wide association studies analysis displayed no significant association between the DHX36 gene and other phenotypes. These genes potentially regulate CA by influencing specific metabolite levels. Molecular docking results indicated good binding affinity between multiple candidate drugs and proteins encoded by the target genes. Our study identified nine potential drug targets associated with CA, with four targets further supported for reliability. Given the roles of these genes in inflammation and metabolic regulation, drug development targeting these genes holds significant clinical potential. This study provides genetic evidence supporting the potential therapeutic benefits of targeting four druggable genes for CA treatment, which will aid in the development of CA drugs.