Cytochrorne P4502C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects
Cytochrorne P4502C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects
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DOI：
10.1182/blood-2006-04-013052
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发表时间：
2006-10-01
期刊：
影响因子：
20.3
通讯作者：
Gaussem, Pascale
中科院分区：
文献类型：
--
作者：
Hulot, Jean-Sebastien;Bura, Alessandra;Gaussem, Pascale
氯吡格雷抑制adp诱导的血小板聚集的能力显示出广泛的主体间变异性。为了确定参与氯吡格雷代谢激活的候选细胞色素P450 （CYP）同位酶编码基因的频繁功能变异（CYP2C19*2、CYP2B6*5、CYP1A2*1F和CYP3A5*3变异）是否影响血小板对氯吡格雷的反应性，我们对28名健康白人男性志愿者进行了一项前瞻性药物遗传学研究，受试者接受氯吡格雷75mg /d治疗7天。我们观察到氯吡格雷的药效学反应与CYP2C19基因型显著相关。其中20例为野生型CYP2C19（*1 /* 1）纯合子，8例为功能缺失多态性CYP2C19*2（*11*2）杂合子。基线血小板活性不受CYP2C19基因型的影响。相比之下，*1/*1受试者在服用氯吡格雷75 mg / 1次/ d治疗期间，10 μ M ADP存在下的血小板聚集逐渐下降，第7天达到48.9% +/- 14.9%（与基线相比P < 0.001），而*1/*2受试者的血小板聚集没有变化（第7天为71.8% +/- 14.6%，与基线相比P = 0.22，与*1/*1受试者相比P < 0.003）。VASP磷酸化也有类似的结果。CYP2C19*2功能缺失等位基因与年轻健康男性志愿者血小板对氯吡格雷反应性显著降低有关，因此可能是临床氯吡格雷耐药的重要遗传因素。
The capacity of clopidogrel to inhibit ADP-induced platelet aggregation shows wide intersubject variability. To determine whether frequent functional variants of genes coding for candidate cytochrome P450 (CYP) isoenzymes involved in clopidogrel metabolic activation (CYP2C19*2, CYP2B6*5, CYP1A2*1F, and CYP3A5*3 variants) influence the platelet responsiveness to clopidogrel, we conducted a prospective pharmacogenetic study in 28 healthy white male volunteers treated for 7 days with clopidogrel 75 mg/d. We observed that pharmacodynamic response to clopidogrel was significantly associated with the CYP2C19 genotype. Twenty of the subjects were wild-type CYP2C19 (*l/*l) homozygotes, while the other 8 subjects were heterozygous for the loss-of-function polymorphism CYP2C19*2(*11*2). Baseline platelet activity was not influenced by the CYP2C19 genotype. In contrast, platelet aggregation in the presence of 10 mu M ADP decreased gradually during treatment with clopidogrel 75 mg once daily in *1/*1 subjects, reaching 48.9% +/- 14.9% on day 7 (P < .001 vs baseline), whereas it did not change in *1/*2 subjects (71.8% +/- 14.6% on day 7, P = .22 vs baseline, and P < .003 vs *1/*1 subjects). Similar results were found with VASP phosphorylation. The CYP2C19*2 loss-of-function allele is associated with a marked decrease in platelet responsiveness to clopidogrel in young healthy male volunteers and may therefore be an important genetic contributor to clopidogrel resistance in the clinical setting.