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Isolation of Endocardial and Coronary Endothelial Cells from the Ventricular Free Wall of the Rat Heart
Published on: April 15, 2020
Integrative analysis of vascular endothelial cell genomic features identifies AIDA as a coronary artery disease
Simon Lalonde1, Valérie-Anne Codina-Fauteux1,2, Sébastian Méric de Bellefon1,2
1Montreal Heart Institute, 5000 Belanger street, Montréal, Québec, H1T 1C8, Canada.
Insights
Genetic variants linked to coronary artery disease (CAD) and blood pressure (BP) influence endothelial cells. This study maps these variants to regulatory elements, revealing their role in vascular disease risk.
Area of Science:
- Genomics
- Cardiovascular Science
- Cell Biology
Background:
- Genome-wide association studies (GWAS) have identified numerous loci for coronary artery disease (CAD) and blood pressure (BP), but their functional mechanisms are often unclear.
- Many identified loci lack links to traditional risk factors or obvious candidate genes, hindering functional characterization.
- Endothelial cells are crucial for vascular homeostasis, and their dysfunction is implicated in atherosclerosis and hypertension, suggesting a role for endothelial-specific gene regulation in vascular diseases.
Purpose of the Study:
- To investigate the hypothesis that GWAS loci associated with vascular diseases modulate endothelial cell functions.
- To create an integrated map of gene expression, open chromatin, and 3D interactions in human endothelial cells under resting and inflammatory conditions.
- To identify regulatory elements in endothelial cells that harbor genetic variants associated with CAD and BP.
Main Methods:
- Generation of an integrated map of gene expression, open chromatin regions, and 3D genome interactions in human endothelial cells.
- Analysis of enrichment of CAD and BP single nucleotide polymorphisms (SNPs) within endothelial cell open chromatin regions.
- Utilizing Hi-C data to link open chromatin regions containing disease-associated SNPs to gene promoters.
- Validation of a CAD locus using CRISPR/Cas9 gene editing to assess the impact on gene expression.
Main Results:
- Genetic variants associated with CAD and BP are significantly enriched in open chromatin regions of endothelial cells.
- Identification of 991 regulatory element-gene promoter combinations linked to 38 CAD and 92 BP GWAS loci.
- Successful validation of a CAD-associated regulatory element's role in modulating the expression of a novel candidate gene, AIDA.
Conclusions:
- Genetic variants acting within the vascular endothelium play a significant role in modulating individual risk for CAD and hypertension.
- The findings highlight the importance of endothelial cell-specific regulatory elements in the genetic architecture of vascular diseases.
- This study provides a valuable resource for understanding the functional impact of GWAS findings in vascular biology.
Background:
Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD) and blood pressure (BP) or hypertension. Many of these loci are not linked to traditional risk factors, nor do they include obvious candidate genes, complicating their functional characterization. We hypothesize that many GWAS loci associated with vascular diseases modulate endothelial functions. Endothelial cells play critical roles in regulating vascular homeostasis, such as roles in forming a selective barrier, inflammation, hemostasis, and vascular tone, and endothelial dysfunction is a hallmark of atherosclerosis and hypertension. To test this hypothesis, we generate an integrated map of gene expression, open chromatin region, and 3D interactions in resting and TNFα-treated human endothelial cells.
Results:
We show that genetic variants associated with CAD and BP are enriched in open chromatin regions identified in endothelial cells. We identify physical loops by Hi-C and link open chromatin peaks that include CAD or BP SNPs with the promoters of genes expressed in endothelial cells. This analysis highlights 991 combinations of open chromatin regions and gene promoters that map to 38 CAD and 92 BP GWAS loci. We validate one CAD locus, by engineering a deletion of the TNFα-sensitive regulatory element using CRISPR/Cas9 and measure the effect on the expression of the novel CAD candidate gene AIDA.
Conclusions:
Our data support an important role played by genetic variants acting in the vascular endothelium to modulate inter-individual risk in CAD and hypertension.
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