Identification of key genes for cuproptosis in carotid atherosclerosis
Xize Wu1,2, Jian Kang2, Xue Pan2,3
1Department of Critical Care Medicine, Nantong Hospital of Traditional Chinese Medicine, Nantong Hospital Affiliated to Nanjing University of Chinese Medicine, Nantong, Jiangsu, China.
Insights
Cuproptosis influences the carotid atherosclerosis (CAS) immune microenvironment and actin cytoskeleton. This study identifies key genes and develops a nomogram for predicting CAS incidence and plaque stability.
Area of Science:
- Cardiovascular Biology
- Molecular Pathology
- Genomics
Background:
- Atherosclerosis, a global cardiovascular disease, includes carotid atherosclerosis (CAS) as a major cause of stroke.
- Emerging research links cuproptosis, a cell death pathway, to increased risk of atherosclerotic cardiovascular disease.
- Understanding the molecular mechanisms connecting cuproptosis and CAS is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the potential mechanisms linking cuproptosis to carotid atherosclerosis (CAS).
- To identify key genes and pathways involved in cuproptosis-related CAS.
- To develop a predictive model for CAS incidence and plaque stability.
Main Methods:
- Integrated gene expression datasets (GSE100927, GSE43292) to identify CAS differentially expressed genes (DEGs).
- Intersected CAS DEGs with cuproptosis-related genes to identify CAS cuproptosis-related genes (CASCRGs).
- Employed unsupervised clustering, weighted gene co-expression network analysis, and machine learning (Lasso + XGBoost) for gene screening and nomogram construction.
Main Results:
- Identified four ASCRGs (NLRP3, SLC31A2, CDKN2A, GLS) regulating the CAS immune microenvironment.
- Discovered two distinct cuproptosis-related molecular clusters in CAS samples.
- Validated SGCE, PCDH7, RAB23, and RIMKLB as hub genes, with SGCE and PCDH7 serving as biomarkers for CAS plaque stability.
Conclusions:
- Cuproptosis significantly alters the immune infiltration microenvironment in carotid atherosclerosis.
- Cuproptosis may play a regulatory role in actin cytoskeleton formation within CAS.
- A developed nomogram demonstrates satisfactory predictive performance for CAS incidence.
Background:
Atherosclerosis is a leading cause of cardiovascular disease worldwide, while carotid atherosclerosis (CAS) is more likely to cause ischemic cerebrovascular events. Emerging evidence suggests that cuproptosis may be associated with an increased risk of atherosclerotic cardiovascular disease. This study aims to explore the potential mechanisms linking cuproptosis and CAS.
Methods:
The GSE100927 and GSE43292 datasets were merged to screen for CAS differentially expressed genes (DEGs) and intersected with cuproptosis-related genes to obtain CAS cuproptosis-related genes (CASCRGs). Unsupervised cluster analysis was performed on CAS samples to identify cuproptosis molecular clusters. Weighted gene co-expression network analysis was performed on all samples and cuproptosis molecule clusters to identify common module genes. CAS-specific DEGs were identified in the GSE100927 dataset and intersected with common module genes to obtain candidate hub genes. Finally, 83 machine learning models were constructed to screen hub genes and construct a nomogram to predict the incidence of CAS.
Results:
Four ASCRGs (NLRP3, SLC31A2, CDKN2A, and GLS) were identified as regulators of the immune infiltration microenvironment in CAS. CAS samples were identified with two cuproptosis-related molecular clusters with significant biological function differences based on ASCRGs. 220 common module hub genes and 1,518 CAS-specific DEGs were intersected to obtain 58 candidate hub genes, and the machine learning model showed that the Lasso + XGBoost model exhibited the best discriminative performance. Further external validation of single gene differential analysis and nomogram identified SGCE, PCDH7, RAB23, and RIMKLB as hub genes; SGCE and PCDH7 were also used as biomarkers to characterize CAS plaque stability. Finally, a nomogram was developed to assess the incidence of CAS and exhibited satisfactory predictive performance.
Conclusions:
Cuproptosis alters the CAS immune infiltration microenvironment and may regulate actin cytoskeleton formation.
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