Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Australia.
Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
Thromb Haemost. 2022 Jul;122(7):1130-1138. doi: 10.1055/a-1711-1395. Epub 2021 Dec 1.
Protease-activated receptor 4 (PAR4) is a platelet thrombin receptor important for thrombosis and a target of antiplatelet drug development. A frequently occurring single-nucleotide polymorphism (rs773902) causes a PAR4 sequence variant (NC_000019.10:p.Ala120Thr) whereby platelets from Thr120-expressing individuals are hyperresponsive to PAR4 agonists versus platelets from Ala120-expressing individuals. However, whether this enhanced platelet responsiveness translates to increased thrombotic risk or decreased bleeding risk remains unknown.
This article examines the association of rs773902 with adjudicated cardiovascular events and aspirin use in a randomized trial population of healthy older individuals.
We analyzed 13,547 participants in the ASPirin in Reducing Events in the Elderly trial. Participants had no previous cardiovascular events at enrollment and were randomized to either 100 mg daily aspirin or placebo for a median follow-up of 4.7 years. Total genotypes were 8,761 (65%) GG (Ala120 variant), 4,303 (32%) heterozygotes, and 483 (4%) AA (Thr120 variant). Cox proportional hazard regression tested the relationship between rs773902 and thrombotic events (major adverse cardiovascular events [MACE] and ischemic stroke [IS]) and bleeding (major hemorrhage [MHEM] and intracranial bleeding [ICB]).
No statistically significant association was observed overall or by treatment group between rs773902 and any thrombotic or bleeding event examined. Further, there was no significant interaction between rs773902 and treatment for any of MACE, IS, MHEM, or ICB.
This post hoc analysis of a prospective cohort study suggests that, despite sensitizing platelet activation, the rs773902 PAR4 variant is not associated with thrombotic cardiovascular or bleeding events in a healthy older population.
蛋白酶激活受体 4（PAR4）是一种血小板血栓素受体，对血栓形成很重要，也是抗血小板药物开发的靶点。一种常见的单核苷酸多态性（rs773902）导致 PAR4 序列变异（NC_000019.10：p.Ala120Thr），从而使表达 Thr120 的血小板对 PAR4 激动剂的反应性高于表达 Ala120 的血小板。然而，这种增强的血小板反应性是否转化为更高的血栓形成风险或更低的出血风险尚不清楚。
本文研究了 rs773902 与一项健康老年人群随机试验人群中经裁决的心血管事件和阿司匹林使用的相关性。
我们分析了 REDUCE 试验中的 13547 名参与者。参与者在入组时无先前的心血管事件，并随机分配至每天 100mg 阿司匹林或安慰剂，中位随访时间为 4.7 年。总基因型为 8761 例（65%）GG（Ala120 变异）、4303 例（32%）杂合子和 483 例（4%）AA（Thr120 变异）。Cox 比例风险回归检验了 rs773902 与血栓形成事件（主要不良心血管事件 [MACE] 和缺血性卒中 [IS]）和出血（大出血 [MHEM] 和颅内出血 [ICB]）之间的关系。
总体或按治疗组，rs773902 与任何研究中观察到的血栓形成或出血事件均无统计学显著相关性。此外，rs773902 与任何 MACE、IS、MHEM 或 ICB 之间也无显著的治疗相互作用。
这项前瞻性队列研究的事后分析表明，尽管 PAR4 变体 rs773902 可使血小板激活致敏，但在健康老年人群中，该变体与血栓性心血管或出血事件无关。
