Frequency of genetic polymorphisms of COX1, GPIIIa and P2Y1 in a Chinese population and association with attenuated response to aspirin
Frequency of genetic polymorphisms of COX1, GPIIIa and P2Y1 in a Chinese population and association with attenuated response to aspirin
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中国人群COX1、GPIIIa和P2Y1基因多态性频率及其与阿司匹林反应减弱的关系
DOI：
10.2217/14622416.8.6.577
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发表时间：
2007-06-01
期刊：
影响因子：
2.1
通讯作者：
Zhou, Hong-Hao
中科院分区：
文献类型：
--
作者：
Li, Qing;Chen, Bi-Lian;Zhou, Hong-Hao
背景：阿司匹林是一种常用的处方药，用于心肌梗死、卒中和心血管死亡的一级和二级预防。然而，阿司匹林抵抗可能影响高达45%的人口。在不同人群中，对阿司匹林抵抗或增强反应的遗传因素的作用知之甚少。研究方法：在来自中国大陆的非吸烟、无药物的健康志愿者的大样本中，（n = 323;年龄：22.1 +/- 2.0岁）（平均标准差），我们确定了环氧合酶1（COX 1）多态性的频率，（A-842 G和C50 T）、糖蛋白IIIa（GPIIIa）（PLA 1/A2）和嘌呤能受体P2 Y（P2 Y1）（C893 T和A1622 G）基因。这些候选基因的选择是基于它们对血小板生理学和阿司匹林作用模式的影响。从上述大型研究样本中确定的4组P2 Y1基因型分层的健康志愿者样本（共n = 24）前瞻性接受每日100 mg口服剂量的阿司匹林，持续7天。我们测量了阿司匹林治疗前后血小板聚集的变化。作为比较参考组，在前瞻性阿司匹林试验中的24名受试者中有6名具有P2 Y1 CT 893/AG 1622基因型，其在中国人群中显示出低频率（< 7%）。结果：在中国大陆人群中未发现COX 1 A-842 G、C50 T和GPIIIa PLAVA 2基因多态性。P2 Y1893 T和1622 G等位基因频率分别为3.5%和30.6%。在本研究中观察到的P2 YI A1622 G多态性的杂合性是不同的高加索人，中国人显示出较高的等位基因频率为1622 G等位基因。阿司匹林治疗后，P2 Y1 CT 893/AG 1622基因型组中花生四烯酸诱导的血小板聚集的净减少显著更大与CC 893/GG 1622相比（83.4 +/-3.7%，阿司匹林的净降低以基线百分比表示）（68.2 +/- 13.5%）、CC 893/AG 1622（68.9 +/- 9.6%）和CC 893/AA 1622（65.1 +/-9.1%）基因型组（分别为p = 0.012、0.025和0.004;统计功效= 77%）。阿司匹林的抗血小板作用在CC 893/GG 1622、CC 893/AG 1622和CC 893/AA 1622基因型间差异无统计学意义（p > 0.05）。结论：COX 1A-842 G、C50 T和GPIIIa PLAVA 2基因多态性在中国人中较为少见。与之前在高加索人群中的研究相反，这些候选功能多态性不太可能是中国人阿司匹林药效学的重要贡献者。重要的是，P2 YI 893 CC基因型的存在似乎在健康中国志愿者阿司匹林治疗期间赋予减弱的抗血小板作用。这些数据共同强调了临床药物遗传学研究中群体间变异的重要性，并为进一步长期研究阿司匹林反应和心血管风险患者的P2 Y1遗传变异提供了基础。
Background: Aspirin is a frequently prescribed drug for primary and secondary prevention of myocardial infarction, stroke and cardiovascular death. However, aspirin resistance may affect up to 45% of the population. Little is known on the role of genetic factors that contribute to resistance or augmented response to aspirin in different human populations. Methods: In a large sample of nonsmoker, medication-free healthy volunteers from mainland China (n = 323; age: 22.1 +/- 2.0 years) (mean standard deviation), we determined the frequency of polymorphisms in cyclooxygenase 1 (COX1) (A-842G and C50T), glycoprotein IIIa (GPIIIa) (PLA1/A2) and purinergic receptor P2Y (P2Y1) (C893T and A1622G) genes. These candidate genes were chosen on the basis of their impact on platelet physiology and aspirin mode of action. A four panel P2Y1 genotype-stratified sample of healthy volunteers (n = 24 in total), identified from the large study sample above, prospectively received a 100 mg daily oral dose of aspirin for 7 days. We measured changes in platelet aggregation before and after aspirin treatment. As a comparison reference group, 6 out of 24 subjects in the prospective aspirin trial had the P2Y1 CT893/AG1622 genotype that displays a low frequency (< 7%) in the Chinese population. Results: COX1 A-842G, C50T and GPIIIa PLAVA2 genetic polymorphisms were not observed in our sample from mainland China. Allele frequencies of P2Y1 893T and 1622G were 3.5 and 30.6%, respectively. The heterozygosity for the P2YI A1622G polymorphism observed in the present study was different to Caucasians; Chinese displayed a higher allele frequency for the 1622G allele. After aspirin treatment, the net decrease in arachiclonic acid-induced platelet aggregation was significantly larger in the P2Y1 CT893/AG1622 genotype panel (83.4 +/- 3.7%, net reduction by aspirin expressed as percentage of baseline) compared with CC893/GG1622 (68.2 +/- 13.5%), CC893/AG1622 (68.9 +/- 9.6%) and CC893/AA1622 (65.1 +/- 9.1 %) genotypic groups (p = 0.012, 0.025 and 0.004, respectively; statistical power = 77%). There was no significant difference in antiplatelet effect of aspirin among the CC893/GG1622, CC893/AG1622 and CC893/AA1622 genotypes (p > 0.05). Conclusions: The COX1 A-842G, C50T and GPIIIa PLAVA2 polymorphisms are rare in Chinese. In contrast to previous studies in Caucasian populations, these candidate functional polymorphisms are unlikely to be significant contributors to aspirin pharmacodynamics in Chinese persons. Importantly, the presence of the P2YI 893CC genotype appears to confer an attenuated antiplatelet effect during aspirin treatment in healthy Chinese volunteers. These data collectively underscore the importance of population-to-population variability in clinical pharmacogenetics research and provide a basis for further long-term studies of aspirin response and P2Y1 genetic variation in patients with cardiovascular risk.