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Identification of Potential Therapeutic Targets for Coronary Atherosclerosis from an Inflammatory Perspective Through
Hesong Wang1, Fengzhe Xie2, Meng Wang1
1Department of Biostatistics, School of Public Health, Harbin Medical University, Harbin 150081, China.
Abstract:
Coronary atherosclerosis (CAS) is a major cause of cardiovascular morbidity worldwide. The understanding of atherosclerosis has shifted from a cholesterol deposition disorder to an inflammation-driven disease, with anti-inflammatory therapies demonstrating clinical efficacy. Identifying inflammatory protein targets is crucial for developing targeted therapies. A proteome-wide Mendelian randomization (MR) analysis was performed to explore therapeutic targets for CAS by integrating inflammatory proteomics data from the UK-PPP (54,219 participants, 2923 proteins) and Iceland cohorts (35,559 participants, 4907 proteins) as exposures and outcome data for CAS, atherosclerosis, and carotid atherosclerosis from FinnGen. Replication MR employed meta-analysis of six proteomics datasets and CAS data from three sources, while the impact of the identified proteins on four cardiovascular diseases was also investigated. Colocalization analysis (PPH4 > 0.9), reverse MR, and SMR were used to ensure robust causal inference. Proteome-wide MR identified 11 proteins significantly associated with CAS (p < 3.52 × 10-5), with all but CD4 linked to cardiovascular disease risk. Notably, colocalization confirmed the causal roles of PCSK9, IL6R, CELSR2, FN1, and SPARCL1 in CAS, and single-cell RNA-seq analysis revealed that five genes (TGFB1, SPARCL1, IL6R, FN1, and CELSR2) were exclusively expressed in smooth muscle cells of either coronary plaques or healthy vasculature. Druggability assessments were subsequently conducted for these targets. The three most promising targets (CELSR2, FN1, and SPARCL1), along with the other identified proteins and their biological functions, exhibit robust causal associations with CAS. FN1 and TGFB1 have the potential for drug repurposing in atherosclerosis treatment.
Insights
This study identifies 11 inflammatory proteins causally linked to coronary atherosclerosis (CAS). Three promising targets, CELSR2, FN1, and SPARCL1, show potential for developing new anti-inflammatory therapies for cardiovascular disease.
Area of Science:
- Cardiovascular Genetics
- Proteomics
- Inflammation Biology
Background:
- Coronary atherosclerosis (CAS) is a leading cause of global cardiovascular disease.
- Understanding CAS has evolved, recognizing inflammation as a key driver, necessitating identification of novel therapeutic targets.
- Anti-inflammatory strategies are increasingly important in managing atherosclerosis.
Purpose of the Study:
- To identify novel, inflammation-related protein targets for coronary atherosclerosis (CAS) using a proteome-wide Mendelian randomization (MR) approach.
- To validate causal associations and explore the therapeutic potential of identified proteins.
- To investigate the expression patterns and druggability of candidate proteins.
Main Methods:
- Proteome-wide Mendelian randomization (MR) analysis integrating large-scale proteomics and CAS outcome data from UK-PPP, Iceland, and FinnGen cohorts.
- Replication MR using meta-analysis of multiple proteomics and CAS datasets.
- Colocalization, reverse MR, and SMR analyses for robust causal inference.
- Single-cell RNA-seq for gene expression analysis in vascular cells.
- Druggability assessments for identified protein targets.
Main Results:
- Proteome-wide MR identified 11 proteins significantly associated with CAS (p < 3.52 × 10^-5), with most linked to cardiovascular disease risk.
- Colocalization analysis confirmed causal roles for PCSK9, IL6R, CELSR2, FN1, and SPARCL1 in CAS.
- Five genes (TGFB1, SPARCL1, IL6R, FN1, CELSR2) showed specific expression in smooth muscle cells of coronary plaques or healthy vasculature.
- CELSR2, FN1, and SPARCL1 emerged as promising therapeutic targets, with FN1 and TGFB1 identified for potential drug repurposing.
Conclusions:
- This study provides robust evidence for 11 inflammation-related proteins causally associated with coronary atherosclerosis.
- CELSR2, FN1, and SPARCL1 represent promising therapeutic targets for novel anti-atherosclerosis treatments.
- The findings support the development of targeted anti-inflammatory therapies for CAS, with potential for drug repurposing.
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