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

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. Electronic supplementary material The online version of this article (10.1186/s13059-019-1749-5) contains supplementary material, which is available to authorized users.

CRISPR perturbations at many coronary artery disease loci impair vascular endothelial cell functions

“…The functional characterization of two CAD genes in endothelial cells, PLPP3 10 and MIA3/AIDA 9 , has further supported this hypothesis. Vascular endothelial cells have critical roles in atherosclerosis 9,11,12 . Upon activation, they express adhesion molecules necessary for monocyte rolling and attachment ( e.g.…”

“…CC-BY-NC-ND 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted February 11, 2021. ; https://doi.org/10.1101/2021.02.10.430527 doi: bioRxiv preprint 9 in the FES promoter and overlaps an ATAC-seq peak as well as a H3K27ac-defined enhancer that physically interacts with the FURIN promoter ( Figure 4A) 9 . The same SNP is an eQTL for FES in human primary aortic endothelial cells 23 and arterial tissues from GTEx.…”

“…Half of the CAD GWAS loci do not associate with traditional risk factors. We and others have hypothesized that some of the CAD variants, which are enriched in open chromatin regions found in human vascular endothelial cells, directly modulate endothelial cell functions [5][6][7][8][9] . The functional characterization of two CAD genes in endothelial cells, PLPP3 10 and MIA3/AIDA 9 , has further supported this hypothesis.…”

“…Vascular endothelial cells have critical roles in atherosclerosis 9,11,12 . Upon activation, they express adhesion molecules necessary for monocyte rolling and attachment (e.g.…”

“…We and others have hypothesized that some of the CAD variants, which are enriched in open chromatin regions found in human vascular endothelial cells, directly modulate endothelial cell functions 5–9 . The functional characterization of two CAD genes in endothelial cells, PLPP3 10 and MIA3/AIDA 9 , has further supported this hypothesis. Vascular endothelial cells have critical roles in atherosclerosis 9,11,12 .…”