Genomic Markers of Cerebral Small Vessel Ischemia

Principal Investigator
Brunham, Liam (Department of Medicine, University of British Columbia)

Mentor
Nadia Khan

Network Affiliation
Canadian Vascular Network

 

1. The Health Problem/Issue

Damage to the small blood vessels of the brain is a major contributor to stroke and dementia. While risk factors for vascular disease such as smoking, diabetes, high blood pressure and elevated cholesterol contribute to small vessel disease, we currently lack methods to identify patients at risk of developing this condition. As a consequence, damage to the small blood vessels of the brain is typically not identified until a patient has already had a stroke or developed dementia, or these changes are detected on a CT scan or MRI of a patient's brain. By that point, meaningful intervention to prevent or reverse these changes may be too late. There is therefore an urgent need to develop new methods to identify patients at risk of small vessel disease early on to allow intervention to reduce the risk of neurological damage. Unlike a blood test or an x-ray, an individual's genome (the collection of all of the DNA in their cells) is stable throughout his or her lifetime. A genomic marker that predicts risk of small vessel disease would therefore allow early identification of patients at risk and could lead to strategies to reduce the risk of dementia and stroke. Up to 80% of the variability in small-vessel disease has been estimated to be due to genetic differences, but the specific genes that influence this risk have not yet been identified.
 

2. The Objectives 

The overall goal of this research program is to identify genomic markers that predict small vessel disease of the brain. Specifically we will investigate patients that have had strokes or dementia due to small vessel disease, or who have brain imaging showing evidence of damage to the small blood vessels of the brain, compared to patients with no such damage. We will search for DNA variants that are associated with the risk of small vessel disease of the brain.
 

3. The Approach

Because small vessel disease is associated with heart disease and shares many risk factors with heart disease, we will examine patients with a history of premature heart disease as well as their family members to identify individuals with small vessel disease of the brain. These patients will be identified through a large province-wide registry called SAVE BC. We will employ targeted sequencing of candidate genes to search for genomic signatures that correlate with small vessel disease.
 

4. The Unique Factors 

While it is known that genetics plays an important role in small vessel disease, no major study has identified the specific genomic regions that predict this process. Our study could therefore be the first to identify an important DNA marker that predicts the risk of developing small vessel disease of the brain leading to stroke or dementia. This could lead directly to the development of new diagnostic tests that could identify patients early in life who are at risk of developing small vessel disease. This would be particularly useful for patients with a personal or family history of vascular disease.
 

5. How the project is relevant to the objectives of the initiative 

Small vessel disease is a major risk factor for stroke and in addition can lead to vascular dementia and bleeding in the brain. Strategies to identify patients at risk for small vessel disease are urgently needed to reduce the burden of these diseases. This work is therefore of direct relevance to vascular disease and stroke.
 

6. The Impact

By identifying a DNA based marker that predicts the risk of small vessel disease we will be able to test patients early on in life to identify individuals at risk of this disease. These patients could receive intensive lifestyle and medical intervention to reduce their risk of ultimately developing these devastating neurological consequences. This research could therefore have substantial impact on the care of patients with stroke. This is likely to be particularly relevant to patients with a personal or family history of vascular disease who are at high risk for small vessel disease and often live with the uncertainty of whether they will have a stroke or develop dementia. Using genomic technologies to identify patients at risk will both alleviate this uncertainty and ensure that medical interventions are targeted to the most appropriate patients with the ultimate goal of reducing the burden of vascular disease and stroke in our communities.
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