# A genetic approach to identify the common mechanisms of vascular disease

> **NIH NIH DP2** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $68,349

## Abstract

Project Summary
 In my clinical training, I repeatedly saw the devastating effects of vascular disease on
patients in the prime of their lives. Vascular diseases such as coronary artery disease
(CAD), stroke, arterial dissection, and migraine headache combine to cause over half the
death and disability in the United States1. To eradicate vascular disease it will be
important to develop new treatments that target the arterial cells where the disease
begins. The disease-causing pathways in these cells may be common to all vascular
diseases, and their shared genetic risk can be a window into this pathophysiology. The
loci associated with multiple vascular diseases have recently been identified through
genome-wide association studies (GWAS). These loci represent new therapeutic targets,
but their biological mechanisms remain largely unexplored. There are multiple challenges
that exist for identifying these disease-causing biological mechanisms. First, each
association often involves multiple variants. Second, most causal variants occur in non-
coding regions, where the associated gene is unclear. Third, the relevant cell type is often
critical for determining the function of a variant. I have identified new opportunities to
address each of these challenges by integrating methods in GWAS analysis, single cell
RNA-sequencing, and genome-editing of vascular cells. I utilized this approach to study
the regulatory effect of the 6p24 locus on endothelin-1 expression, and aim to extend this
unique combination of methods to the full set of pleiotropic vascular loci. This New
Innovator Award application seeks to understand the intersecting mechanisms of multiple
vascular diseases from the functional analysis of human genetic variation. The analytic
pipeline I propose will prioritize loci with pleiotropic effects on three vascular diseases,
and interrogate their combined effects on vascular cell function. I will establish an analytic
pipeline to identify common vascular disease-associated loci and functionally
characterize their biological effects. This will establish a new approach to the prioritization
and functional characterization of vascular disease-causing variants, and identify new
biological pathways for the treatment of multiple vascular diseases.

## Key facts

- **NIH application ID:** 10477676
- **Project number:** 3DP2HL152423-01S1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** RAJAT M GUPTA
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $68,349
- **Award type:** 3
- **Project period:** 2019-09-01 → 2022-08-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477676

## Citation

> US National Institutes of Health, RePORTER application 10477676, A genetic approach to identify the common mechanisms of vascular disease (3DP2HL152423-01S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10477676. Licensed CC0.

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