Integrative analysis of vascular endothelial cell genomic features identifies AIDA as a coronary artery disease candidate gene.
Genome Biol
; 20(1): 133, 2019 07 08.
Article
en En
| MEDLINE
| ID: mdl-31287004
ABSTRACT
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.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Enfermedad de la Arteria Coronaria
/
Proteínas de Transferencia de Fosfolípidos
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Genome Biol
Asunto de la revista:
BIOLOGIA MOLECULAR
/
GENETICA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Canadá