The Cardeza Foundation for Hematologic Research and Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Nat Med. 2013 Dec;19(12):1609-16. doi: 10.1038/nm.3385. Epub 2013 Nov 10.
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.
种族间动脉粥样血栓形成的病理生理学差异尚未被充分了解。我们研究了健康的黑种人（n=70）和白种人（n=84）血小板的功能和转录组。PAR4 凝血酶受体诱导的血小板聚集和钙动员在黑种人中显著增加。许多差异表达的 RNA 与种族和 PAR4 反应性相关，包括 PCTP（编码磷脂酰胆碱转移蛋白），并且黑种人的血小板表达更高水平的 PC-TP 蛋白。PC-TP 抑制或耗竭可阻断 PAR4 而非 PAR1 介导的血小板和巨核细胞系的激活。miR-376c 的表达水平因种族和 PAR4 反应性而异，与 PCTP mRNA 水平、PC-TP 蛋白水平和 PAR4 反应性呈负相关。miR-376c 调节人类巨核细胞中 PC-TP 的表达。有相当数量的 microRNAs 因种族和 PAR4 反应性而差异表达，包括 miR-376c，这些 microRNAs 编码在 DLK1-DIO3 基因座中，并且在黑种人的血小板中表达水平较低。这些结果表明，PC-TP 有助于 PAR4 介导的血小板激活中的种族差异，表明血小板功能的基因组贡献因种族而异，并强调在开发抗血栓药物时需要考虑种族的影响。
