A common, racially diverse protease activated receptor 4 functional variant impacts ischemic stroke outcomes: evidence for a pharmacogenetic effect

Frederik Roland Denorme, Ph.D.
University of Utah
Salt Lake City, UT, U.S.

Protease activated receptor (PAR) 4 harbors a functional dimorphism, rs773902 A/G (encoding Thr120/Ala120, respectively), and is associated with greater platelet reactivity. The hyperreactive A allele is more common in Black individuals, and Black individuals have a higher incidence of ischemic stroke than white individuals. However, it is unknown whether the A allele impacts stroke incidence or outcomes.

In a prospective study of 7,620 Black subjects with 487 incident ischemic strokes, we found the AA genotype was a risk for incident ischemic stroke and worse functional outcomes after stroke. To directly test the effect of this variant on stroke, we generated mice expressing human PAR4 (hPAR4) instead of mouse PAR4, with either Thr120 or Ala120. Compared to hPAR4 Ala120 mice, hPAR4 Thr120 mice had hyperreactive platelets and worse stroke outcomes. Next, we assessed the efficacy of standard antiplatelet drugs commonly used to treat ischemic stroke patients. In our humanized mice, treatment with ticagrelor with or without aspirin improved stroke outcomes in hPAR4 Ala120 mice but not in hPAR4 Thr120 mice. However, targeting platelet-neutrophil interactions with a P-selectin inhibitor improved stroke outcomes equally in hPAR4 Ala120 and Thr120 mice.

In conclusion, our results may explain some of the racial disparity in stroke and support the need for studies of nonstandard antiplatelet therapies for patients expressing PAR4 Thr120.