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| Status |
Public on Jun 25, 2019 |
| Title |
Integrative vascular endothelial cell genomics identify AIDA as a coronary artery disease candidate gene (RNAseq) |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Genome-wide association studies (GWAS) have identified 100s of loci associated with coronary artery disease (CAD) and blood pressure (BP)/hypertension. Many of these loci are not associated with traditional risk factors, nor include obvious candidate genes, complicating their functional characterization. We hypothesized that many GWAS loci associated with vascular diseases modulate endothelial functions. Endothelial cells play critical roles in regulating vascular homeostasis (e.g. selective barrier, inflammation, hemostasis, vascular tone) and endothelial dysfunction is a hallmark of atherosclerosis and hypertension. We generated an integrated map of gene expression (RNA-sequencing), open chromatin regions (ATAC-sequencing), and 3D interactions (Hi-C) in resting and TNFα-treated human endothelial cells. We showed that genetic variants associated with CAD and BP are enriched in open chromatin regions identified in endothelial cells. We used physical loops identified by Hi-C to link open chromatin peaks that include CAD or BP SNPs with the promoter of genes expressed in endothelial cells. This analysis highlighted 4,548 combinations of regulatory elements-promoters, including 108 pairs that involve a differentially open chromatin site and a differentially expressed gene following TNFα treatment. At a CAD locus, we validated one of these pairs by engineering a deletion of the TNFα-sensitive regulatory element using CRISPR/Cas9 and measuring an effect on the expression of the novel CAD candidate gene AIDA. Our data support an important role played by genetic variants acting in the vascular endothelium to modulate inter-individual risk in CAD or hypertension
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| Overall design |
RNAseq of TNF-alpha treated endothelial cells (teloHAEC and HCAEC) for 0, 4h or 24h
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| Contributor(s) |
Lalonde S, Codina-Fauteux V, Méric de Bellefon S, Leblanc F, Beaudoin M, Dali R, Kwan T, Sin Lo K, Pastinen T, Lettre G |
| Citation(s) |
31287004 |
| |
| Submission date |
Feb 06, 2019 |
| Last update date |
Sep 24, 2019 |
| Contact name |
Guillaume Lettre |
| E-mail(s) |
Guillaume.Lettre@mhi-humangenetics.org
|
| Organization name |
Montreal Heart Institute
|
| Street address |
5000 Rue Bélanger
|
| City |
Montreal |
| State/province |
Quebec |
| ZIP/Postal code |
H1T 1C8 |
| Country |
Canada |
| |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE126200 |
Integrative vascular endothelial cell genomics identify AIDA as a coronary artery disease candidate gene |
|
| Relations |
| BioProject |
PRJNA521270 |
| SRA |
SRP184297 |
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