# Systems Genetics of Vascular Smooth Muscle Phenotypes

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $515,509

## Abstract

PROJECT SUMMARY
Coronary artery disease (CAD) remains the leading cause of death in the Western world despite significant
advances in early detection and extensive use of lipid-lowering and anti-hypertensive drugs. To date, no single
drug has been developed to target the primary disease process in the vessel wall. A complete understanding
of the disease susceptibility is urgently needed to develop additional therapies. Common forms of
atherosclerosis involve environmental factors, hundreds of genetic variations, and their interactions, each of
which exert a relatively small effect on disease susceptibility. The most recent genome-wide association study
(GWAS) in nearly six hundred fifty thousand individuals identified 175 independent variants associated with
increased risk for CAD. However, most of the underlying genes and the related mechanisms of how these
variants contribute to the disease process remain unknown. This proposal outlines an integrative genetics
study in a unique resource of human aortic smooth muscle cells (SMCs) isolated from 151 genotyped multi-
ethnic heart transplant donors to discover the CAD-associated variants that perturb SMC gene expression and
their downstream functional consequences. In recent studies, we measured gene expression in quiescent and
proliferative culture conditions representing the transdifferentiation of SMCs from a healthy to an atherogenic
phenotype. We identified 84 genes whose expression was associated with CAD variants in GWAS loci.
However, the causal genetic variants in these loci remain to be elucidated. Therefore, as part of the proposed
studies, we will first perform massively parallel reporter assays to identify the variants that modulate gene
expression in SMCs. We will also take advantage of the natural variation in gene expression to construct co-
expression and Bayesian networks to understand how the predicted candidate causal genes function in SMCs.
We will refine these networks by mapping regulatory elements to nascent RNA transcripts in response to pro-
inflammatory cytokines. We will then validate our predictions in gain and loss-of-function experiments in
cultured SMCs. We will also validate our predictions in well-phenotyped coronary artery specimens from cases
of unexpected sudden death by performing immunohistochemical analysis of proteins encoded by genes that
are predicted to play a key role in atherosclerosis-relevant SMC phenotypes. The overall goal of the proposed
studies is to integrate systems genetics and computational biology leading to mechanistic predictions of the
gene networks that are perturbed by CAD. Besides understanding CAD loci, these integrative genetics studies
will provide a useful window into the flow of biological information from genetic variants to SMC gene
expression and atherosclerosis-relevant phenotypes.

## Key facts

- **NIH application ID:** 10753508
- **Project number:** 5R01HL166428-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Mete Civelek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $515,509
- **Award type:** 5
- **Project period:** 2022-12-15 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10753508

## Citation

> US National Institutes of Health, RePORTER application 10753508, Systems Genetics of Vascular Smooth Muscle Phenotypes (5R01HL166428-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10753508. Licensed CC0.

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