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Updated: May 14, 2025
Quantitative Analysis of Cellular Composition in Advanced Atherosclerotic Lesions of Smooth Muscle Cell Lineage-Tracing Mice
Published on: February 20, 2019
Identifying Potential Drug Targets in Coronary Atherosclerosis: Insights from the Druggable Genome and Mendelian
Ruikang Liu1,2, Chiyun Sun2,3, Jun Li4
1Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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.
Insights
Researchers identified five genes (VAMP8, MFGE8, PDGFD, GGCX, NPEPPS) as potential therapeutic targets for coronary atherosclerosis (CA). This study explored their mechanisms, risks, and potential new indications for CA treatment.
Area of Science:
- Genetics and Genomics
- Cardiovascular Research
- Pharmacogenomics
Background:
- Coronary atherosclerosis (CA) poses a significant global health burden.
- Identifying novel therapeutic targets is crucial for effective CA management.
- Understanding the genetic underpinnings and pathophysiological mechanisms of CA is essential.
Purpose of the Study:
- To identify novel druggable genes for coronary atherosclerosis (CA) using publicly available datasets.
- To explore the pathophysiologic mechanisms, mediators, and potential side effects of identified therapeutic targets.
- To evaluate the causal relationship between gene expression quantitative trait loci (eQTL) and CA.
Main Methods:
- Two-sample Mendelian randomization (MR) and single-cell MR analyses were performed.
- Expression quantitative trait loci (eQTL) and peripheral protein quantitative trait loci (pQTL) data were integrated.
- Summary data-based MR (SMR), HEIDI tests, mediation MR, and phenotype-wide MR (Phe-MR) were utilized.
Main Results:
- Five genes (VAMP8, MFGE8, PDGFD in peripheral tissues; GGCX, NPEPPS in central tissues) were identified as CA-associated.
- Single-cell MR revealed cell-type-specific associations for GGCX and NPEPPS with CA risk.
- Phe-MR analysis suggested potential indications and side effects for the identified targets.
Conclusions:
- VAMP8, MFGE8, PDGFD, GGCX, and NPEPPS are presented as potential therapeutic targets for coronary atherosclerosis.
- The study highlights the clinical relevance, associated risks, and mediators of these targets.
- Findings provide valuable insights for developing novel CA therapeutics.
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