Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race
Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race
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DOI：
10.1182/blood-2014-04-572479
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发表时间：
2014-11-27
期刊：
影响因子：
20.3
通讯作者：
Bray, Paul F.
中科院分区：
文献类型：
--
作者：
Edelstein, Leonard C.;Simon, Lukas M.;Bray, Paul F.
人血小板表达2种凝血酶受体：蛋白酶激活受体（PAR）-1和PAR 4。最近，我们报道了与白色受试者相比，黑人受试者血小板中PAR 4介导的聚集动力学增加了3.7倍。我们现在发现，来自黑人（n = 70）的血小板比来自白人（n = 84）的血小板多表达14%的PAR 4蛋白，但这种差异与血小板PAR 4功能无关。数量性状基因座分析确定了3个常见的单核苷酸多态性在PAR 4基因（F2 RL 3）与PAR 4诱导的血小板聚集。在这些单核苷酸多态性中，rs773902决定跨膜结构域2中的残基120是丙氨酸（Ala）还是苏氨酸（Thr）。与Ala 120变体相比，Thr 120在黑人受试者中比在白色受试者中更常见（63%对19%），与更高的PAR 4诱导的人血小板聚集和Ca 2+通量相关，并在转染细胞中产生更大的肌醇1，4，5-三磷酸。第二种频率较低的F2 RL 3变体Phe 296 Val仅在黑人中观察到，并消除了增强的PAR 4诱导的血小板聚集和与PAR 4-Thr 120相关的1，4，5-三磷酸生成。PAR 4基因型不影响vorapaxar对血小板PAR 1功能的抑制作用，但在PAR 4特异性拮抗剂YD-3 [1-苄基-3（ethoxycarbonylphenyl）-indazole]中观察到强烈的药物遗传学效应。这些发现可能对开发新的PAR拮抗剂具有重要的药物遗传学作用。
Human platelets express 2 thrombin receptors: protease-activated receptor (PAR)-1 and PAR4. Recently, we reported 3.7-fold increased PAR4-mediated aggregation kinetics in platelets from black subjects compared with white subjects. We now show that platelets from blacks (n = 70) express 14% more PAR4 protein than those from whites (n = 84), but this difference is not associated with platelet PAR4 function. Quantitative trait locus analysis identified 3 common single nucleotide polymorphisms in the PAR4 gene (F2RL3) associated with PAR4-induced platelet aggregation. Among these single nucleotide polymorphisms, rs773902 determines whether residue 120 in transmembrane domain 2 is an alanine (Ala) or threonine (Thr). Compared with the Ala120 variant, Thr120 was more common in black subjects than in white subjects (63% vs 19%), was associated with higher PAR4-induced human platelet aggregation and Ca2+ flux, and generated greater inositol 1,4,5-triphosphate in transfected cells. A second, less frequent F2RL3 variant, Phe296Val, was only observed in blacks and abolished the enhanced PAR4-induced platelet aggregation and 1,4,5-triphosphate generation associated with PAR4-Thr120. PAR4 genotype did not affect vorapaxar inhibition of platelet PAR1 function, but a strong pharmacogenetic effect was observed with the PAR4-specific antagonist YD-3 [1-benzyl-3(ethoxycarbonylphenyl)-indazole]. These findings may have an important pharmacogenetic effect on the development of new PAR antagonists.