Document Type

Article

Publication Date

7-8-2019

Identifier

DOI: 10.1186/s13059-019-1749-5; PMCID: PMC6613242

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.

Journal Title

Genome biology

Volume

20

Issue

1

First Page

133

Last Page

133

MeSH Keywords

CRISPR-Cas Systems; Coronary Artery Disease; Endothelial Cells; Epigenomics; Genome-Wide Association Study; Humans; Phospholipid Transfer Proteins; Regulatory Elements, Transcriptional; Transcriptome

Keywords

AIDA; Blood pressure; CRISPR/Cas9; Coronary artery disease; Endothelial dysfunction; Genome-wide association study; Hi-C; Hypertension; Vascular endothelium

Comments

Grant support

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Publisher's Online Access: https://doi.org/10.1186/s13059-019-1749-5

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