Identifying Potential Drug Targets in Coronary Atherosclerosis: Insights from the Druggable Genome and Mendelian Randomization.

Abstract

Purpose: This study aims to identify therapeutic targets for coronary atherosclerosis (CA) using publicly available datasets while exploring its pathophysiologic mechanisms, mediators and potential side effects.

Methods: We conducted a two-sample Mendelian randomization (MR) and single-cell MR analyses integrating identified druggable genes to evaluate the causal relationship between expression quantitative trait loci (eQTL) and CA in both peripheral and central tissues. Using peripheral protein quantitative trait loci (pQTL) data, we further validated the identified targets at the proteomic level through summary data-based MR (SMR) and HEIDI tests. Concurrently, mediation MR analysis was employed to investigate potential mechanistic pathways underlying the role of these targets in CA. Additionally, a phenotype-wide MR (Phe-MR) analysis was performed to explore other potential indications for the therapeutic application of the identified targets.

Results: In conclusion, we identified three CA-associated genes in peripheral tissues (VAMP8, MFGE8 and PDGFD) two CA-associated genes in central tissues (GGCX and NPEPPS). In addition, single-cell MR analyses revealed that GGCX was associated with increased CA risk in excitatory, inhibitory and oligodendrocyte precursor cells, whereas NPEPPS was associated with protection in oligodendrocyte lineage cells. Finally, Phe-MR analyses indicated possible indications and side effects of the targets.

Conclusion: Our study provides genetic evidence for VAMP8, MFGE8, PDGFD, GGCX and NPEPPS as potential therapeutic targets for CA, highlighting their clinical relevance, associated risks and mediators, and providing valuable insights for the development of novel CA therapeutics.