Liu Ruikang, Sun Chiyun, Li Jun, Yang Guangyi, Xu Ke, Hu Jiaming, Meng Chao, Xia Xiao, Li Yonghao, Liu Yiying
Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
Graduate School, Beijing University of Chinese Medicine, Beijing, China.
Cardiovasc Drugs Ther. 2025 Apr 11. doi: 10.1007/s10557-025-07694-1.
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.
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.
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.
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.
本研究旨在利用公开可用数据集确定冠状动脉粥样硬化（CA）的治疗靶点，同时探索其病理生理机制、介导因素和潜在副作用。
我们进行了两样本孟德尔随机化（MR）和单细胞MR分析，并整合已确定的可成药基因，以评估外周和中枢组织中表达数量性状位点（eQTL）与CA之间的因果关系。利用外周蛋白质数量性状位点（pQTL）数据，我们通过基于汇总数据的MR（SMR）和HEIDI检验在蛋白质组学水平进一步验证已确定的靶点。同时，采用中介MR分析来研究这些靶点在CA中作用的潜在机制途径。此外，还进行了全表型MR（Phe-MR）分析，以探索已确定靶点治疗应用的其他潜在适应症。
总之，我们在外周组织中确定了三个与CA相关的基因（VAMP8、MFGE8和PDGFD），在中枢组织中确定了两个与CA相关的基因（GGCX和NPEPPS）。此外，单细胞MR分析显示，GGCX在兴奋性、抑制性和少突胶质细胞前体细胞中与CA风险增加相关，而NPEPPS在少突胶质细胞谱系细胞中与保护作用相关。最后，Phe-MR分析表明了这些靶点可能的适应症和副作用。
我们的研究为VAMP8、MFGE8、PDGFD、GGCX和NPEPPS作为CA的潜在治疗靶点提供了遗传学证据，突出了它们的临床相关性、相关风险和介导因素，并为新型CA治疗药物的开发提供了有价值的见解。
