C-reactive protein, molecular models
At a Glance
- Gene variants could signal an increased stroke risk
- With a better understanding of stroke genetics, more tailored therapeutics will arise
- A blood test may now be used to predict recurrent stroke
A Window Into the Biology of Stroke
As you’re probably well aware, stroke remains the fifth leading cause of death in the U.S. and is the leading cause of disability in adults. UVA researchers have turned to genetics to learn more about the biology of ischemic stroke — which accounts for about 85 percent of all strokes in this country — in order to understand more about its risk factors, identify new ways to prevent its occurrence and target new drug and other therapies.
“We know a lot about risk factors,” says Bradford B. Worrall, MD, MSc, director of the Acute Stroke Intervention Team at UVA Health System. He says hypertension, smoking, age, gender and even geography can factor into stroke risk. “But as much as 50 percent of our risk for stroke remains unaccounted for. So we have to look for other reasons for the unexplained risk. Genetics is appealing for that.”
Stroke is not a disorder that is caused by a single gene variant, so research is focused broadly, searching for a combination of genetic and epigenetic factors.
The term “ischemic stroke” represents a collection of several stroke subtypes, including those caused by large artery atherosclerosis, cardioembolic events (usually cerebral embolism arising from atrial fibrillation), small vessel disease of the penetrating vessels of the brain and a significant group of cryptogenic strokes whose mechanisms remain unclear. Each of these subtypes may have its own set of genetic influences, while some gene variants may be relevant in several of these subtypes.
To pinpoint what Worrall describes as the “window into the biology” that will allow researchers to identify ways to alter the disease process, they must analyze data from tens of thousands of cases. Worrall and others at UVA have joined together with investigators around the world to form consortia that share data and work together to sort through it. Using genetic profiles of stroke patients from several sources, these researchers from the National Institutes of Health’s Stroke Genetics Network (SiGN) and the International Stroke Genetics Consortium have developed leads on several unexpected gene loci that appear to be important in understanding stroke.
Among the most exciting recent findings is the discovery of a gene variation associated with increased risk for recurrent stroke. It has been known for some time that patients with high levels of C-reactive protein (CRP) in their blood are at higher risk for both stroke and coronary disease. UVA geneticist Stephen Williams, PhD, found evidence to support the idea that this biomarker doesn’t just indicate the presence of stroke-related disease, such as atherosclerosis. Elevated levels of CRP, a component of the normal inflammatory response, may be a good predictor of a person’s risk for actually having a stroke.
These findings offer exciting insights into the disease, insights that Worrall says will soon allow clinicians to tailor treatment to the individual case. For clinicians, accurately diagnosing stroke subtype becomes even more important as research into the genetics of stroke refines our understanding of these subtypes and how they can be approached therapeutically.
For example, “some of the genetics look like they’re going to show us shared risk between subtypes,” Worrall says. “Small vessel disease and cardioembolic events are typically thought to be unrelated. But if there’s a gene that increases the risk of both, that may challenge our clinical categories. We’re not there yet, but knowing more about the biology is going to help us identify which patients will benefit the most from certain therapies.”
So while the ability to predict who will have a stroke is still a long way off, UVA’s genetic stroke research is making it more likely that genetic information will soon be useful in predicting a patient’s response to treatment as well as in developing new therapies.
“This work is giving us really great insight into the mechanisms of this disease,” Worrall says. “We’re also on the verge of being able to translate some of the earliest findings into potential treatments. These are really exciting times.”
To learn more, watch the video below: