The predominant PAR4 variant in individuals of African ancestry worsens murine and human stroke outcomes

• Published in: The Journal of clinical investigation Vol. 133; no. 18; pp. 1 - 18
• Main Authors: Denorme, Frederik, Armstrong, Nicole D., Stoller, Michelle L., Portier, Irina, Tugolukova, Emilia A., Tanner, Rikki M., Montenont, Emilie, Bhatlekar, Seema, Cody, Mark, Rustad, John L., Ajanel, Abigail, Tolley, Neal D., Murray, Darian C., Boyle, Julie L., Nieman, Marvin T., McKenzie, Steven E., Yost, Christian Con, Lange, Leslie A., Cushman, Mary, Irvin, Marguerite R., Bray, Paul F., Campbell, Robert A.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.09.2023
• Subjects: Africans; Aggregation; Alleles; Analysis; Animals; Aspirin; Biomedical research; Blood platelets; Blood Platelets - physiology; Cell activation; Cell receptors; Dimorphism; Ethnicity; Gene frequency; Genetic aspects; Genetic variation; Genotypes; Health aspects; Hematology; Humans; Ischemia; Ischemic Stroke; Leukocytes (neutrophilic); Medical research; Medicine, Experimental; Mice; Neuroscience; Neutrophils; Physiological aspects; Platelet aggregation; Platelet Aggregation - genetics; Platelet Aggregation Inhibitors - pharmacology; Proteases; Proteins; Race; Receptor, PAR-1; Receptors, Thrombin - genetics; Risk factors; Stroke; Stroke (Disease); Stroke - genetics; United States; Utah; Neuroscience; Stroke; Hematology; Drug therapy; Platelets
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI169608

Protease-activated receptor 4 (PAR4) (gene F2RL3) harbors a functional dimorphism, rs773902 A/G (encoding Thr120/Ala120, respectively) and is associated with greater platelet aggregation. The A allele frequency is more common in Black individuals, and Black individuals have a higher incidence of ischemic stroke than White individuals. However, it is not known whether the A allele is responsible for worse stroke outcomes. To directly test the in vivo effect of this variant on stroke, we generated mice in which F2rl3 was replaced by F2RL3, thereby expressing human PAR4 (hPAR4) with either Thr120 or Ala120. Compared with hPAR4 Ala120 mice, hPAR4 Thr120 mice had worse stroke outcomes, mediated in part by enhanced platelet activation and platelet-neutrophil interactions. Analyses of 7,620 Black subjects with 487 incident ischemic strokes demonstrated the AA genotype was a risk for incident ischemic stroke and worse functional outcomes. In humanized mice, ticagrelor with or without aspirin improved stroke outcomes in hPAR4 Ala120 mice, but not in hPAR4 Thr120 mice. P selectin blockade improved stroke outcomes and reduced platelet-neutrophil interactions in hPAR4 Thr120 mice. 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.