# Multimodal genetic regulatory architecture of coronary artery disease

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $742,087

## Abstract

PROJECT SUMMARY
Coronary artery disease (CAD) remains a global public health burden despite advances in risk factor targeted
therapies. Meta-analyses across ancestrally diverse populations have identified >300 genetic loci associated
with CAD risk. We and others have investigated candidate genes that are dysregulated in the coronary
vascular wall; however, the causal genes and regulatory mechanisms remain mostly unknown. Recent
advances in single-cell genomics profiling have begun to unravel the cellular diversity during atherosclerosis.
Molecular quantitative trait (QTL) mapping and gene regulatory network approaches in disease-relevant
tissues have refined some of the regulatory mechanisms, however the specific cell types and phenotypic states
driving these changes remain unclear. We have leveraged a large biobank of coronary artery tissues from
ancestrally diverse individuals to perform bulk and single-cell profiling of genetic variation and cell states. Using
single-nucleus profiling of chromatin accessibility in healthy and subclinical atherosclerotic coronary arteries we
identified cis-regulatory elements to explain transitions of smooth muscle cells (SMC) to fibroblast-like cell
types. By meta-analyzing single-cell gene expression data in atherosclerosis, we have also identified etiologic
SMC phenotypic states underlying CAD as well as coronary artery calcification (CAC). Here we propose to
extend our previous efforts to apply multimodal single-cell profiling to capture QTLs and gene regulatory
mechanisms in both subclinical and advanced atherosclerotic coronary segments. Building on our holistic
framework and resources, this proposal will generate unprecedented insights into the hierarchical regulatory
networks that influence dysregulated vascular wall processes. By enriching these high-resolution data with
large-scale population genetics, clinical imaging, and genomic and histologic cardiometabolic tissue biobanks
we will provide context for translating these findings to patients at various stages of disease. We have already
identified several disease stage and cell state-specific markers for atherosclerosis. We will validate and
discover new candidate causal genes and functional regulatory elements using perturbation assays coupled to
high-throughput phenotyping in SMC, along with spatial imaging in intact tissues across the disease trajectory.
Together with our interdisciplinary and experienced collaborators and unique established resources, we are
well-positioned to carry out this work and discover fine-grained molecular features and hallmarks of CAD
initiation and progression in the coronary vessel wall. Ultimately, these studies will enable the next generation
of multimodal treatment strategies for risk stratification and eradication of this debilitating disease.

## Key facts

- **NIH application ID:** 10980582
- **Project number:** 2R01HL148239-06
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Clint L Miller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $742,087
- **Award type:** 2
- **Project period:** 2019-06-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980582

## Citation

> US National Institutes of Health, RePORTER application 10980582, Multimodal genetic regulatory architecture of coronary artery disease (2R01HL148239-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10980582. Licensed CC0.

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