# Leveraging  the Genetics of carotid stenosis for identifying novel risk factors and therapeutic opportunities

> **NIH VA I01** · PHILADELPHIA VA MEDICAL CENTER · 2024 · —

## Abstract

Current guidelines for primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD),
including coronary heart disease (CHD), peripheral artery disease (PAD), and cerebrovascular disease, focus
on the uniform application of risk factor modification irrespective of CVD subtype, despite rising evidence that
each of these diseases has specific underlying pathobiology. Large scale genetic studies have identified new
biology, clarified the role of modifiable risk factors, improved risk prediction, and identified therapeutic targets for
CHD and PAD. This work has demonstrated vascular territory specific effects of risk factors and therapies,
motivating disease specific approaches to prevention and treatment of atherosclerotic cardiovascular disease.
Unfortunately, genetic studies of cerebrovascular disease have lagged. Extant studies have tended to focus on
either early-stage subclinical atherosclerosis (carotid intima to media thickness [cIMT]) or late-stage outcomes
(ischemic stroke). Studies of actual atherosclerotic cerebrovascular disease, in the form of carotid stenosis, have
been limited by small sample size.
The VA Million Veteran Program (MVP) was initiated in 2011 to study how genes, lifestyle, and military exposure
affect health and disease and offers a unique opportunity to advance the genetics of atherosclerotic
cerebrovascular disease through the study of carotid stenosis. To do this we have developed a validated natural
language processing (NLP) algorithm to extract quantitative measures of carotid stenosis severity from imaging
reports in the VA electronic health record (EHR), facilitating the study of both disease susceptibility and
progression. The overarching hypothesis of this proposal is that the development of carotid plaque, progression
of stenosis, and resulting ischemic stroke represent distinct pathobiological states, each offering a separate
opportunity for therapeutic intervention. To address this hypothesis, we will conduct genome-wide association
studies of both disease susceptibility and progression. The results from these analyses will be then used for
genetic causal inference experiments to: 1. Quantify the causal impact of traditional risk factors on the
susceptibility to carotid stenosis; 2. Determine the causal risk factors for the progression of carotid stenosis; and
3. Identify the shared genetic architecture of carotid stenosis and ischemic stroke using genomic structural
equation modeling.
Successfully completion of this project will clarify the role of traditional risk factors with carotid stenosis, identify
novel opportunities for prevention and treatment, and establish the basis for tailored, precision medicine
approaches to the treatment of carotid stenosis and stroke prevention for Veterans.

## Key facts

- **NIH application ID:** 10863814
- **Project number:** 5I01BX006159-02
- **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER
- **Principal Investigator:** Scott Michael Damrauer
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863814

## Citation

> US National Institutes of Health, RePORTER application 10863814, Leveraging  the Genetics of carotid stenosis for identifying novel risk factors and therapeutic opportunities (5I01BX006159-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10863814. Licensed CC0.

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