# From genotype to phenotype in a GWAS locus: the role of REST in atherosclerosis

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2024 · $171,720

## Abstract

Project Summary
This K08 mentored clinical scientist research career development award is a five-year program designed to
facilitate Dr. Marios Arvanitis’ (PI) development into an independent physician-investigator in vascular genetics.
 Atherosclerotic cardiovascular disease (ASCVD) is a major public health burden that accounts for over
600,000 deaths in the United States each year. ASCVD is highly heritable and genome-wide association studies
have discovered many candidate genomic loci that increase the risk of the disease in the population, thereby
providing a window to novel therapies. However, most genomic risk loci for ASCVD remain unexplored in terms
of how they lead to disease risk.
 Previously published work by the PI has focused on the mechanistic interpretation of genomic risk loci
for cardiovascular disease, including the development of a novel Bayesian method, called CAFEH, to prioritize
the target tissue and genes in genomic loci. Our preliminary analyses of the genetic underpinnings of ASCVD
reveal that endothelial cells are enriched for ASCVD heritability, and we have used those methods to prioritize a
chromosome 4 locus that is predicted to affect ASCVD risk via altering the expression of the RE-1 silencing
transcription factor (REST) gene in endothelial cells. This K08 project will explore the regulatory mechanisms via
which the REST locus and gene influence the development of atherosclerosis. Aim 1 will employ CRISPR-Cas9
editing in human stem cells which will then be differentiated into endothelial cells to identify the causal variants
and the upstream transcription factors that mediate the association in the 4q12 coronary disease GWAS locus.
Aim 2 will define distal genes and pathways affected by REST in the endothelium and investigate their cellular
consequences, starting with evaluating the role of REST in endothelial to mesenchymal transition. Aim 3 will use
a tamoxifen inducible endothelial specific Rest knock-out mouse model to evaluate the in vivo effects of Rest in
the endothelium and atherosclerosis.
 The success of this project is guaranteed by the support of a multidisciplinary mentoring team including
a vascular biologist (Dr. Charles Lowenstein), a computational biologist (Dr. Alexis Battle), and a functional
genetics expert (Dr. Andrew McCallion), along with an advisory committee of experts in vascular biology, stem
cell differentiation and atherosclerosis (Dr. Harry Dietz, Dr. Chulan Kwon and Dr. Thomas Quertermous). This
award period will help the PI boost their genomics skills, acquire new wet lab skills and generate preliminary data
to successfully compete for R01 funding in order to translate the genetic insights into novel mechanisms for
ASCVD.

## Key facts

- **NIH application ID:** 10769836
- **Project number:** 5K08HL166690-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Marios Arvanitis
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $171,720
- **Award type:** 5
- **Project period:** 2023-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769836

## Citation

> US National Institutes of Health, RePORTER application 10769836, From genotype to phenotype in a GWAS locus: the role of REST in atherosclerosis (5K08HL166690-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10769836. Licensed CC0.

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