In a new study, researchers have demonstrated that a particular version of a gene may contribute to the higher severity of stroke seen among Black Americans.
It is hoped that these findings from researchers at the University of Utah could help scientists develop more effective stroke medications for people who carry the gene.
The research, demonstrated that mice carrying the gene had an increased level of disability after a stroke. These mice were also less responsive to drugs commonly used to prevent stroke. The results are the first direct evidence linking the gene to medical outcomes.
Robert Campbell, senior author of the study, says: “This suggests one novel reason for racial disparities in stroke outcomes is that standard anti-platelet therapies may not be appropriate for patients carrying this gene, which includes around 60% of Black patients.”
Gene ‘turbo-charges’ blood clotting
Black Americans have a higher risk of stroke than other ethnic groups and a higher rate of death and disability after a stroke. Lifestyle factors and other comorbid medical conditions contribute to this disparity, but previous research has also shown that genetics play a role.
This version of a gene involved in blood clotting, called PAR4, is common in Black individuals. It’s estimated that around 60 per cent of Black individuals and 20% of White individuals have the A allele version of this gene.
PAR4 works by helping blood cells, called platelets, form clots. These clumps of cells are important to help stop bleeding after injury but can cause stroke if they obstruct the flow of blood in the brain. PAR4 sits on the surface of platelets and detects chemical signals released into the blood to activate clot formation.
Other studies have shown that platelets from Black individuals often recruited many more platelets when exposed to the clotting signal compared with platelets from White donors. This led researchers to suspect that the A allele could be “turbo-charging” the platelets, leading to larger clots and worse stroke outcomes.
To investigate this idea, the researchers looked at data from a large-scale observational study of stroke risk factors in humans. When they tested 7,620 Black participants for PAR4, they found that individuals carrying two copies of the A allele had a higher incidence of stroke and higher levels of disability afterward.
In order to dig deeper, the scientists turned to mice. Working with the pre-clinical model allowed them to control for other genetic and environmental factors, something that’s not possible in humans. This meant they could isolate the effects of just one genetic change.
Campbell, says: “It’s all association until you can prove it from a molecular biology perspective.”
The researchers found that, as they had predicted, platelets from mice carrying the PAR4 A allele had heightened reactivity. Clots formed larger clusters compared with platelets from mice who were completely identical except for that one gene. Mice with the A allele also had greater disability after a stroke.
Differential drug activity
From there, the scientists tested stroke-preventing medications on the mice with the two “humanised” versions of the PAR4 gene.
First author of the study, Frederik Denorme, says: “That’s where I think it becomes really interesting.”
FDA-approved medications commonly prescribed to prevent stroke, such as aspirin and ticagrelor, protected mice with the PAR4 variant that is common in Whites. But the drugs did not protect mice carrying the PAR4 variant common in Black individuals.
However, it is too soon for the new findings to change clinical practice, but Denorme says he hopes the study impacts how clinical research is carried out. Clinical trials often enroll mostly White patients, meaning genes that are more common in other populations are not well represented. Boosting racial diversity in trials can reveal when a drug’s activity varies among groups, he says.
Denorme believes that the mouse model could be useful for testing possible new medications to improve stroke outcomes in people.
Denorme, says: “These mice will allow us to address questions like why one drug is not good for all stroke patients.
“I think our project hints at the need for personalised medicine based on genetics.”
- The next century. Those areas may include technology-driven health care and diagnostics (i.e., artificial intelligence/machine learning approaches, telemedicine, biosensors and wearables); novel and emerging therapeutics (i.e., genome editing therapies, regenerative therapies and bioengineered foods); environmental impacts on health (i.e., direct and indirect effects); and research and solutions for issues affecting ageing populations and the shrinking health care workforce. Awardees will also have opportunities to serve on scientific and research councils and committees of the American Heart Association and engage with the Association’s scientific leadership for mentorship connections.
- Clinical Fellow Research Education Program – Directors of 59 accredited cardiology and neurology fellowship programs will receive funding to support training and mentoring opportunities for clinical fellows enrolled in their programs. A fellow is a medical doctor or a doctoral-level health professional who has completed their degree and general residency program and is now training or conducting research in a health specialty. The funding will allow up to five fellows per year from each program to attend the American Heart Association Scientific Sessions or the American Heart Association/American Stroke Association International Stroke Conference, as well engage in as other medical specialty events and activities that will help them gain knowledge and expertise as research scientists.
