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Genetic and immunological insights into COVID-19 with acute myocardial infarction: integrated analysis of mendelian
Zequn Zheng1,2, Yueran Zhou1,2, Yongfei Song3
1Department of Cardiology, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Insights
This study found no genetic link between COVID-19 and acute myocardial infarction (AMI). However, dysregulated TLR4 and ABCA1 genes may drive immune and inflammatory responses in COVID-19 patients experiencing AMI.
Area of Science:
- Cardiovascular Diseases
- Infectious Diseases
- Immunology
- Genetics
Background:
- Cardiovascular diseases are a leading cause of death globally, with ischemic heart disease being particularly prevalent.
- COVID-19 can exacerbate existing heart conditions and cause myocardial injury, increasing the risk of acute myocardial infarction (AMI).
- The precise molecular mechanisms linking COVID-19 to AMI require further investigation.
Purpose of the Study:
- To investigate the potential causal relationship between COVID-19 and AMI using genetic risk assessment.
- To identify shared molecular mechanisms and hub genes underlying both COVID-19 and AMI.
- To characterize the immune cell landscape and molecular pathways involved in COVID-19 associated with AMI.
Main Methods:
- Two-sample Mendelian randomization (TSMR) was employed to assess causality between COVID-19 and AMI.
- Weighted gene co-expression network analysis (WGCNA) and machine learning identified shared hub genes from bulk RNA sequencing (RNA-seq) data.
- Gene set enrichment analysis (GSEA) and single-cell RNA sequencing (scRNA-seq) analyzed immune cell infiltration, communication, and gene expression in clinical samples.
Main Results:
- TSMR did not establish a causal link between COVID-19 and AMI.
- TLR4 and ABCA1 were identified as significant hub genes with diagnostic and predictive value in RNA-seq cohorts.
- scRNA-seq revealed immune dysregulation in COVID-19 patients, with elevated TLR4 and ABCA1 in CD16 monocytes; TLR4 expression was validated in clinical AMI samples from COVID-19 patients.
Conclusions:
- There is no identified genetic causal link between COVID-19 and AMI.
- Dysregulation of TLR4 and ABCA1 may contribute to the immune and inflammatory responses observed in COVID-19 patients with AMI.
Background:
Globally, most deaths result from cardiovascular diseases, particularly ischemic heart disease. COVID-19 affects the heart, worsening existing heart conditions and causing myocardial injury. The mechanistic link between COVID-19 and acute myocardial infarction (AMI) is still being investigated to elucidate the underlying molecular perspectives.
Methods:
Genetic risk assessment was conducted using two-sample Mendelian randomization (TSMR) to determine the causality between COVID-19 and AMI. Weighted gene co-expression network analysis (WGCNA) and machine learning were used to discover and validate shared hub genes for the two diseases using bulk RNA sequencing (RNA-seq) datasets. Additionally, gene set enrichment analysis (GSEA) and single-cell RNA-seq (scRNA-seq) analyses were performed to characterize immune cell infiltration, communication, and immune correlation of the hub genes. To validate the findings, the expression patterns of hub genes were confirmed in clinical blood samples collected from COVID-19 patients with AMI.
Results:
TSMR did not find evidence supporting a causal association between COVID-19 or severe COVID-19 and AMI. In the bulk RNA-seq discovery cohorts for both COVID-19 and AMI, WGCNA's intersection analysis and machine learning identified TLR4 and ABCA1 as significant hub genes, demonstrating high diagnostic and predictive value in the RNA-seq validation cohort. Single-gene GSEA and single-sample GSEA (ssGSEA) revealed immune and inflammatory roles for TLR4 and ABCA1, linked to various immune cell infiltrations. Furthermore, scRNA-seq analysis unveiled significant immune dysregulation in COVID-19 patients, characterized by altered immune cell proportions, phenotypic shifts, enhanced cell-cell communication, and elevated TLR4 and ABCA1 in CD16 monocytes. Lastly, the increased expression of TLR4, but not ABCA1, was validated in clinical blood samples from COVID-19 patients with AMI.
Conclusion:
No genetic causal link between COVID-19 and AMI and dysregulated TLR4 and ABCA1 may be responsible for the development of immune and inflammatory responses in COVID-19 patients with AMI.
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