ArticleThe Journal of clinical investigation2023
The predominant PAR4 variant in individuals of African ancestry worsens murine and human stroke outcomes.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 21 citations in OpenAlex.
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- Immunothrombosis versus thrombo-inflammation: platelets in cerebrovascular complications.Research and practice in thrombosis and haemostasis · 2024Article
- Editorial: Diversity in stroke omic(s) and epidemiology research: opportunities and challenges.Frontiers in stroke · 2024Article
- Immunothrombosis in neurovascular disease.Research and practice in thrombosis and haemostasis · 2024Article
- Targeting PAR4 to Reduce Atherosclerosis.Arteriosclerosis, thrombosis, and vascular biology · 2023Article
- Mouse model hints at pharmacogenomic strategies for stroke treatment in patients possessing a risk variant.The Journal of clinical investigation · 2023Article
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22 authors at 6 institutions in 3 countries.
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Abstract
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.
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