Integrative analysis of vascular endothelial cell genomic features identifies AIDA as a coronary artery disease candidate gene

Genome Biology

卷:20

Tomi Pastinen¹  Tony Kwan²  Marie-Michelle Simon²  Rola Dali²  Sébastian Méric de Bellefon³  Mélissa Beaudoin³  Guillaume Lettre³  Valérie-Anne Codina-Fauteux³  Francis Leblanc³  Simon Lalonde³  Ken Sin Lo³ 

[1] Center for Pediatric Genomic Medicine (CPGM), Children’s Mercy Kansas City;

[2] McGill University and Genome Québec Innovation Center;

[3] Montreal Heart Institute;

关键词: Vascular endothelium;    Endothelial dysfunction;    Coronary artery disease;    Blood pressure;    Hypertension;    Genome-wide association study;   

DOI  :  10.1186/s13059-019-1749-5

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown