在中国接受阿司匹林治疗的缺血性中风患者中，MDR1、TBXA2R、PLA2G7和PEAR1基因多态性与血小板活性的相关性。
Associations of MDR1, TBXA2R, PLA2G7, and PEAR1 genetic polymorphisms with the platelet activity in Chinese ischemic stroke patients receiving aspirin therapy.
作者信息
Peng Ling-Ling, Zhao Yuan-Qi, Zhou Zi-Yi, Jin Jing, Zhao Min, Chen Xin-Meng, Chen Ling-Yan, Cai Ye-Feng, Li Jia-Li, Huang Min
机构信息
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Department of Pharmacy, General Hospital of Guangzhou Military Command of PLA, Guangzhou 510110, China.
出版信息
Acta Pharmacol Sin. 2016 Nov;37(11):1442-1448. doi: 10.1038/aps.2016.90. Epub 2016 Sep 19.
AIM
Aspirin resistance has an incidence of 5%-65% in patients with ischemic stroke, who receive the standard dose of aspirin, but the platelet function is inadequately inhibited, thereby leading to thrombotic events. Numerous evidence shows that thromboxane A receptor (TXA receptor, encoded by TBXA2R), lipoprotein-associated phospholipase A (Lp-PLA, encoded by PLA2G7) and platelet endothelial aggregation receptor-1 (PEAR1, encoded by PEAR1) are crucial in regulating platelet activation, and P-glycoprotein (P-gp, encoded by MDR1) influences the absorption of aspirin in the intestine. In this study we examined the correlation between MDR1, TBXA2R, PLA2G7, PEAR1 genetic polymorphisms and platelet activity in Chinese ischemic stroke patients receiving aspirin therapy.
METHODS
A total of 283 ischemic stroke patients receiving 100 mg aspirin for 7 d were genotyped for polymorphisms in MDR1 C3435T, TBXA2R (rs1131882), PLA2G7 (rs1051931, rs7756935), and PEAR1 (rs12566888, rs12041331). The platelet aggregation response was measured using an automatic platelet aggregation analyzer and a commercially available TXB ELISA kit.
RESULTS
Thirty-three patients (11.66%) were insensitive to aspirin treatment. MDR1 3435TT genotype carriers, whose arachidonic acid (AA) or adenosine diphosphate (ADP)-induced platelet aggregation was lower than that of CC+CT genotype carriers, were less likely to suffer from aspirin resistance (odds ratio=0.421, 95% CI: 0.233-0.759). The TBXA2R rs1131882 CC genotype, which was found more frequently in the aspirin-insensitive group (81.8% vs 62.4%) than in the sensitive group, was identified as a risk factor for aspirin resistance (odds ratio=2.712, 95% CI: 1.080-6.810) with a higher level of AA-induced platelet aggregation. Due to the combined effects of PLA2G7 rs1051931 and rs7756935, carriers of the AA-CC haplotype had a higher level of ADP-induced platelet aggregation, and were at considerably higher risk of aspirin resistance than noncarriers (odds ratio=8.233, 95% CI: 1.590-42.638).
CONCLUSION
A considerable portion (11.66%) of Chinese ischemic stroke patients are insensitive to aspirin treatment, which may be correlated with the MDR1 C3435T, TBXA2R (rs1131882), and PLA2G7 (rs1051931-rs7756935) polymorphisms.
目的
在接受标准剂量阿司匹林治疗的缺血性中风患者中，阿司匹林抵抗的发生率为5% - 65%，这些患者的血小板功能未得到充分抑制，从而导致血栓形成事件。大量证据表明，血栓素A受体（TXA受体，由TBXA2R编码）、脂蛋白相关磷脂酶A（Lp - PLA，由PLA2G7编码）和血小板内皮聚集受体 - 1（PEAR1，由PEAR1编码）在调节血小板活化中起关键作用，而P - 糖蛋白（P - gp，由MDR1编码）影响阿司匹林在肠道的吸收。在本研究中，我们检测了接受阿司匹林治疗的中国缺血性中风患者中MDR1、TBXA2R、PLA2G7、PEAR1基因多态性与血小板活性之间的相关性。
方法
总共283例接受100 mg阿司匹林治疗7天的缺血性中风患者，对其MDR1 C3435T、TBXA2R（rs1131882）、PLA2G7（rs1051931、rs7756935）和PEAR1（rs12566888、rs12041331）的基因多态性进行基因分型。使用自动血小板聚集分析仪和市售的TXB ELISA试剂盒测量血小板聚集反应。
结果
33例患者（11.66%）对阿司匹林治疗不敏感。MDR1 3435TT基因型携带者，其花生四烯酸（AA）或二磷酸腺苷（ADP）诱导的血小板聚集低于CC + CT基因型携带者，发生阿司匹林抵抗的可能性较小（比值比 = 0.421，95%置信区间：0.233 - 0.759）。在阿司匹林不敏感组中比敏感组更频繁发现的TBXA2R rs1131882 CC基因型（81.8%对62.4%），被确定为阿司匹林抵抗的危险因素（比值比 = 2.712，95%置信区间：1.080 - 6.810），其AA诱导的血小板聚集水平较高。由于PLA2G7 rs1051931和rs7756935的联合作用，AA - CC单倍型携带者的ADP诱导的血小板聚集水平较高，与非携带者相比，发生阿司匹林抵抗的风险显著更高（比值比 = 8.233，95%置信区间：1.590 - 42.638）。
结论
相当一部分（11.66%）中国缺血性中风患者对阿司匹林治疗不敏感，这可能与MDR1 C3435T、TBXA2R（rs1131882）和PLA2G7（rs1051931 - rs7756935）基因多态性有关。
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