Racial differences in the pathophysiology of atherothrombosis are poorly understood. We explored the function and transcriptome of platelets in healthy black (n = 70) and white (n = 84) subjects. Platelet aggregation and calcium mobilization induced by the PAR4 thrombin receptor were significantly greater in black subjects. Numerous differentially expressed RNAs were associated with both race and PAR4 reactivity, including PCTP (encoding phosphatidylcholine transfer protein), and platelets from black subjects expressed higher levels of PC-TP protein. PC-TP inhibition or depletion blocked PAR4- but not PAR1-mediated activation of platelets and megakaryocytic cell lines. miR-376c levels were differentially expressed by race and PAR4 reactivity and were inversely correlated with PCTP mRNA levels, PC-TP protein levels and PAR4 reactivity. miR-376c regulated the expression of PC-TP in human megakaryocytes. A disproportionately high number of microRNAs that were differentially expressed by race and PAR4 reactivity, including miR-376c, are encoded in the DLK1-DIO3 locus and were expressed at lower levels in platelets from black subjects. These results suggest that PC-TP contributes to the racial difference in PAR4-mediated platelet activation, indicate a genomic contribution to platelet function that differs by race and emphasize a need to consider the effects of race when developing anti-thrombotic drugs.
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We thank S. McKenzie for helpful discussions, S. Kunapuli (Temple University) for the PAR1 inhibitor, J. Italiano (Harvard Medical School) for the antibody to tubulin, L. Ma for technical support, R. Baserga (Thomas Jefferson University) for the HCT116-Dicer knockout 2 cells and P. Yu for normalizing Affymetrix data. This work was supported by US National Institutes of Health (NIH) grant HL102482 (to P.F.B.) and the Cardeza Foundation for Hematologic Research. Compound A1 was developed with the support of NIH grants DK48873 and DK56626 (to D.E.C.).
The authors declare no competing financial interests.
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Edelstein, L., Simon, L., Montoya, R. et al. Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Nat Med 19, 1609–1616 (2013). https://doi.org/10.1038/nm.3385
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