Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, 410008, Hunan, People's Republic of China.
Eur J Clin Pharmacol. 2021 Mar;77(3):359-368. doi: 10.1007/s00228-020-03024-6. Epub 2020 Oct 21.
Dual antiplatelet therapy with aspirin and clopidogrel is commonly used for coronary artery disease (CAD) patients undergoing percutaneous coronary intervention to prevent stent thrombosis and ischemic events. However, some patients show high on-treatment platelet reactivity (HTPR) during clopidogrel therapy. Genetic factors such as loss-of-function variants of CYP2C19 are validated to increase the risk of HTPR. Flavin-containing monooxygenase 3 (FMO3) is reported to be associated with potency of platelet responsiveness and thrombosis. This study aimed to explore the association between FMO3 rs1736557 polymorphism and clopidogrel response.
Five hundred twenty-two Chinese CAD patients treated with dual antiplatelet therapy were recruited from Xiangya Hospital. After oral administration of 300 mg loading dose (LD) clopidogrel for 12-24 h or 75 mg daily maintenance dose (MD) clopidogrel for at least 5 days, the platelet reaction index (PRI) was determined by vasodilator-stimulated phosphoprotein-phosphorylation assay. FMO3 rs1736557, CYP2C192, and CYP2C193 polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
Mean PRI value was significantly higher in CYP2C19 poor metabolizers (PMs) and intermediate metabolizers (IMs) than the extensive metabolizers (EMs) (p < 0.001). In addition, FMO3 rs1736557 AA homozygotes showed significantly lower PRI as compared with carriers of the major rs1736557 G allele in the entire cohort and in the MD cohort (p = 0.011, p = 0.008, respectively). The risk of HTPR was decreased significantly in carriers of the rs1736557 A allele (AA vs GG: OR = 0.316, 95% CI: 0.137-0.726, p = 0.005; AA vs GA: OR = 0.249, 95% CI: 0.104-0.597, p = 0.001; AA vs GG+GA: OR = 0.294, 95% CI: 0.129-0.669, p = 0.002), and the association was observed mainly in patients carrying the CYP2C19 LOF allele and in those administered with MD.
The FMO3 rs1736557 AA genotype was related to an increased the antiplatelet potency of clopidogrel in Chinese CAD patients. Additional studies are required to verify this finding.
阿司匹林和氯吡格雷双联抗血小板治疗常用于经皮冠状动脉介入治疗的冠心病（CAD）患者，以预防支架血栓和缺血事件。然而，一些患者在氯吡格雷治疗期间表现出高治疗血小板反应性（HTPR）。细胞色素 P450 2C19（CYP2C19）失活变异等遗传因素被证实会增加 HTPR 的风险。黄素单加氧酶 3（FMO3）据报道与血小板反应性和血栓形成的效力有关。本研究旨在探讨 FMO3 rs1736557 多态性与氯吡格雷反应之间的关系。
从湘雅医院招募了 522 名接受双联抗血小板治疗的中国 CAD 患者。在口服 300mg 负荷剂量（LD）氯吡格雷 12-24 小时或每日 75mg 维持剂量（MD）氯吡格雷至少 5 天后，通过血管扩张刺激磷蛋白磷酸化测定法测定血小板反应指数（PRI）。通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）对 FMO3 rs1736557、CYP2C192 和 CYP2C193 多态性进行基因分型。
CYP2C19 弱代谢者（PMs）和中间代谢者（IMs）的平均 PRI 值明显高于强代谢者（EMs）（p<0.001）。此外，在整个队列和 MD 队列中，FMO3 rs1736557 AA 纯合子的 PRI 值明显低于主要 rs1736557 G 等位基因的携带者（p=0.011，p=0.008）。rs1736557 A 等位基因携带者的 HTPR 风险显著降低（AA 与 GG：OR=0.316，95%CI：0.137-0.726，p=0.005；AA 与 GA：OR=0.249，95%CI：0.104-0.597，p=0.001；AA 与 GG+GA：OR=0.294，95%CI：0.129-0.669，p=0.002），这种关联主要见于携带 CYP2C19 失活等位基因的患者和接受 MD 治疗的患者。
在中国 CAD 患者中，FMO3 rs1736557 AA 基因型与氯吡格雷的抗血小板作用增强有关。需要进一步的研究来验证这一发现。
