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

Simon Lalonde,Guillaume Lettre,Rola Dali,Valérie-Anne Codina-Fauteux,Marie-Michelle Simon,Ken Sin Lo,Mélissa Beaudoin,Sébastian Méric De Bellefon,Tony Kwan,Francis Leblanc,Tomi Pastinen

doi:10.1186/s13059-019-1749-5

Abstract

BackgroundGenome-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.ResultsWe 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.ConclusionsOur data support an important role played by genetic variants acting in the vascular endothelium to modulate inter-individual risk in CAD and hypertension.

Highlights

Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD) and blood pressure (BP) or hypertension
Transcriptomic and epigenomic changes in endothelial cells upon activation To develop a tractable endothelial cellular system to study the molecular mechanisms that contribute to the etiology of vascular diseases such as atherosclerosis and hypertension, we characterized the response of teloHAEC to the potent pro-inflammatory cytokine tumor necrosis factor-α (TNFα)
In total when considering all replicates and timepoints, we identified 1316 differentially expressed genes (false discovery rate (FDR) < 0.1% and absolute log10 fold-change (|LFC|) > 0.3)(Fig. 1a for the comparison of NT vs. 4 h TNFα treatment, Additional file 1 for all other comparisons, and Additional file 2 for the complete list of differentially expressed genes)

Summary

Introduction

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. Healthy endothelial cells form a selective barrier between the blood and the intima for many macromolecules, respond to hemodynamic changes, control the vascular tone, and regulate platelet functions, inflammatory responses, and smooth muscle cell growth and migration [14] Despite their pathophysiological importance and the noted overlap with GWAS findings, endothelial cells have not been studied extensively to provide further insights into genotypephenotype associations for CAD and BP/hypertension. We used our datasets to generate mechanistic hypotheses and tested one such prediction at a CAD locus using the CRISPR/Cas genome editing system

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