Investigators from the University of Utah (U of U)Health, reporting in the Journal of Clinical Investigation, say that more severe strokes among Black Americans may be due to a specific gene variant. In their research using mouse models, the U of U Health teams showed that mice carrying the gene had higher levels of disability after stroke and were also less responsive to drugs commonly prescribed to prevent stroke. The research is the first to link the gene directly to medical outcomes.
“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,” said Robert Campbell, PhD, the paper’s senior author and an investigator at U of U Health.
The gene identified in the study, PAR4, is a common variant in Black populations. PAR4 is a culprit in stroke severity as it help platelets in the blood form clots. While clotting is important for stopping bleeding after an injury, clumps of platelets can also become large enough to stop the flow of blood to the brain. PAR4 sits on the surface of platelets and its role is to detect chemical changes in the blood to activate clotting.
While 20% of White individuals also possess the A allele of PAR4, other studies have shown that the platelets in Black patients often recruited many more platelets when exposed to the chemical signal that initiates clotting compared with the platelets of White patients. The U of U Health researchers say this known activity led them to surmise that the A allele could be “turbo-charging the platelets resulting in larger clots and more severe, difficult to treat strokes.
The new research used data from an a broad observational study of stroke risk factors. When 7,620 Black patients were tested for the PAR4 variant, the research showed that people carrying two copies of the A allele had both higher rates of stroke as well as more severe disability.
To build in this finding the investigators then turn to mouse models to allow them to control for genetic and environmental factors, not possible in a human population. As Campbell described it: “It’s all association until you can prove it from a molecular biology perspective.”
Their mouse studies confirmed the hypothesis of the investigators that the PAR4 A allele heightened platelet reactivity and that clots were larger compared with mice who were genetically identical, with the only exception being the PAR4 gene. The result was the mice with the A allele both suffered from stroke more often and had more disability as a result of any stroke.
Armed with this knowledge the U of U Health team then treated mice with the humanized version PAR4 with common medications prescribed by doctors to prevent stroke, such as aspirin and ticagrelor. While these preventive measures protected the mice with the PAR4 variant common to the White populations, they did not protect the mice carrying the PAR4 variant that is found in Black individuals.
According to Frederick DeNorme, PhD, the study’s first author, this new research adds more evidence to the need to add racial diversity to clinical trials in order to reveal those drugs that show varying activity among various racial groups. His hope is that the mouse models developed for this research can be used for further studies to improve stroke outcomes.
“These mice will allow us to address questions like why one drug is not good for all stroke patients,” DeNorme said. “I think our project hints at the need for personalized medicine based on genetics.”
