Gene variant common in black populations linked to severe strokes

A specific allele may contribute to the higher severity of stroke seen among black populations, and also the reason they are less responsive to commonly used stroke medications.

Researchers at the University of Utah Health have found that a version of a gene involved in blood clotting increases the severity of stroke-induced disability. Blood clotting is a process that relies on blood cells called platelets. A specific allele of the PAR4 gene, PAR4 A, is associated with greater platelet aggregation, and thereby greater risk of worse stroke outcomes.

Dr Robert Campbell, senior author of the study, said 'This [study] 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 [allele], which includes around 60 percent of black patients.'

The researchers examined data collected by the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Out of 7620 African-Americans who were followed for ten years on average, 487 experienced an ischaemic stroke. The scientists found that those with two copies of the PAR4 A allele had a greater risk of unfavourable stroke outcome, such as moderate disability or death.

To complement this work, the research team inserted either two PAR4 A alleles or G alleles into genetically identical mice. The G allele is more common in white populations, and the A allele more common in black populations.

They treated mice either with a placebo drug or with common medications that doctors use to prevent stroke: aspirin and ticagrelor. These are both anti-platelet medicines that should make blood less likely to clot, thereby reducing your risk of stroke and unfavourable stroke outcomes.

After inducing stroke in these mice, the research team found that the medications were protective in mice with two G alleles, however, the mice with two A alleles suffered worse stroke outcomes, reminiscent of observations in black populations.

When the researchers examined the platelets from these mice, they found that the PAR4 A mice had greater inflammatory markers and larger clots compared to the PAR4 G mice. This illustrated how the anti-platelet medication had failed to work in the PAR4 A mice, and potentially in humans with this A allele.

Dr Frederik Denorme, first author of the study, added '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.'

While this study is too preliminary to make changes in the clinic, the authors hope that it will impact the diversity of clinical research. Clinical trials predominantly recruit white patients, which limits the genetic diversity of these studies. Increasing the racial diversity of these studies will help identify drugs that are more effective in other groups.

The study was published in the Journal of Clinical Investigation.