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Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c

Nature Medicine volume 19, pages 1609–1616 (2013)Cite this article

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Abstract

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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Figure 1: Racial differences in PAR4-mediated platelet aggregation.
Figure 2: Racial differences in human platelet PC-TP expression and function.
Figure 3: Relationships among racial differences in PAR4 reactivity and transcripts.
Figure 4: miR-376c regulates PCTP expression in megakaryocytes.
Figure 5: A large miRNA cluster in the DLK1-DIO3 region is differentially expressed by race.

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Acknowledgements

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.).

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Authors and Affiliations

  1. The Cardeza Foundation for Hematologic Research and Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

    Leonard C Edelstein, Raúl Teruel Montoya, Michael Holinstat, Xianguo Kong, Srikanth Nagalla & Paul F Bray

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

    Lukas M Simon, Edward S Chen & Chad Shaw

  3. Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

    Angela Bergeron

  4. New York Blood Center, New York, New York, USA

    Narla Mohandas

  5. Department of Medicine, Division of Gastroenterology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    David E Cohen

  6. Puget Sound Blood Center, Seattle, Washington, USA

    Jing-fei Dong

  7. Department of Statistics, Rice University, Houston, Texas, USA

    Chad Shaw

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  1. Leonard C Edelstein
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Contributions

P.F.B. conceived the PRAX1 study. P.F.B. and C.S. designed the PRAX1 study. P.F.B., L.C.E., J.D., C.S. and S.N. supervised the project. L.C.E., L.M.S., E.S.C., R.T.M., M.H., N.M., D.E.C., J.D., C.S. and P.F.B. designed experiments. L.C.E., L.M.S., E.S.C., A.B., X.K., R.T.M. and M.H. collected data. L.C.E., L.M.S. and E.S.C. R.T.M., M.H., J.D., C.S. and P.F.B. analyzed data. L.C.E., E.S.C., D.E.C., C.S. and P.F.B. wrote the manuscript.

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Correspondence to Chad Shaw or Paul F Bray.

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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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