# Cis-regulatory architecture of coronary vascular wall loci

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $405,258

## Abstract

PROJECT SUMMARY
Coronary artery disease (CAD) remains the leading cause of mortality worldwide and poses considerable
public health burden. Both genetic and environmental risk factors contribute to CAD susceptibility, leading to
increased disease prevalence in developing countries. Genome-wide association studies (GWAS) have now
identified 161 independent genetic loci associated with CAD risk in large-scale meta-analyses in over 300,000
individuals. However, given that the majority of the associations reside in non-coding genomic regions, it has
been challenging to translate these discoveries into biologically and clinically relevant insights. Interestingly,
many of the candidate genes at CAD loci are organized into novel or unknown biological pathways, and point
to dysregulation of vascular wall processes. Large efforts such as the Genotype Tissue Expression (GTEx)
project and Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study have
refined candidate gene regulatory mechanisms, however the specific cellular and phenotypic states driving
these changes remains unclear. Smooth muscle cells (SMC) normally regulate vascular tone in the vessel wall
but play critical roles in disease pathogenesis as their contractile gene program is hijacked during phenotypic
switching to macrophage-like and fibroblast-like cells. Using epigenomic and expression quantitative trait loci
(eQTL) mapping in 52 primary human coronary artery smooth muscle cells (HCASMC) we recently identified
11 candidate causal genes and mechanisms linking vascular wall processes to CAD risk (e.g. TCF21, SMAD3,
CDKN2B, LMOD1). It is likely that non-coding regulatory variants function through changes in chromatin
accessibility, which coincides with transcription factor (TF) binding in cis. By identifying these upstream TFs at
vascular wall loci we can begin to assemble targetable pathways to modulate hidden disease risk in the vessel
wall. In this proposal we plan to perform joint gene expression and chromatin accessibility QTL mapping in a
unique cohort of 120 normal and diseased coronary artery tissues from explanted heart donors. We will
validate and discover functional regulatory elements at GWAS loci using CRISPR/dCas9 perturbation with
high-throughput phenotyping in SMC. Finally, we will investigate the cis-regulatory architecture in these
samples at single-cell resolution and infer TF binding during phenotypic modulation. Together these studies will
reveal the causal regulatory mechanisms responsible for CAD in the vascular wall and inform next generation
treatment or prevention strategies to eradicate this debilitating disease.

## Key facts

- **NIH application ID:** 9939642
- **Project number:** 5R01HL148239-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Clint L Miller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,258
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939642

## Citation

> US National Institutes of Health, RePORTER application 9939642, Cis-regulatory architecture of coronary vascular wall loci (5R01HL148239-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9939642. Licensed CC0.

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