Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.
Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy.
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DOI：
10.1001/jama.2009.1232
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发表时间：
2009-08-26
影响因子：
120.7
通讯作者：
Gurbel, Paul A.
中科院分区：
文献类型：
--
作者：
Shuldiner, Alan R.;O'Connell, Jeffrey R.;Bliden, Kevin P.;Gandhi, Amish;Ryan, Kathleen;Horenstein, Richard B.;Damcott, Coleen M.;Pakyz, Ruth;Tantry, Udaya S.;Gibson, Quince;Pollin, Toni I.;Post, Wendy;Parsa, Afshin;Mitchell, Braxton D.;Faraday, Nauder;Herzog, William;Gurbel, Paul A.
氯吡格雷治疗通过抑制二磷酸腺苷（ADP）依赖性血小板活化改善急性冠脉综合征患者和经皮冠状动脉介入治疗后的心血管结局。然而，无反应性被广泛认为与复发性缺血事件有关。确定影响氯吡格雷反应的基因变异。在抗血小板药物基因组学干预（PAPI）研究（2006-2008）中，我们对429名健康阿米什人给予氯吡格雷7天，并通过体外血小板聚集测定法测量反应。进行了全基因组关联研究，然后对功能丧失的细胞色素P450（CYP 2C 19 *2）变体（rs 4244285）进行基因分型。PAPI研究的结果通过在227例接受经皮冠状动脉介入治疗的患者的独立样本中检查CYP 2C 19 *2基因型与血小板功能和心血管结局的关系进行了扩展。ADP刺激的血小板聚集对氯吡格雷治疗和心血管事件的反应血小板对氯吡格雷的反应具有高度遗传性（h=0.73; P<0.001）。CYP 2C 18-CYP 2C 19-CYP 2C 9-CYP 2C 8簇中染色体10 q24上的13个单核苷酸多态性与氯吡格雷反应降低相关，具有高度统计学意义（rs 12777823的P=1.5 × 10−13，相加模型）。rs 12777823多态性与CYP 2C 19 *2变异体存在强连锁不平衡，并与氯吡格雷反应降低相关，占ADP血小板聚集变异的12%（P=4.3 × 10−11）。CYP 2C 19 *2基因型与血小板聚集之间的关系在接受冠状动脉介入治疗的氯吡格雷治疗患者中得到了重复（P= 0.02）。此外，CYP 2C 19 *2变异体患者在1年随访期间更可能（20.9% vs 10.0%）发生心血管缺血事件或死亡（风险比，2.42; 95%置信区间，1.18-4.99; P= 0.02）。CYP 2C 19 *2基因型与血小板对氯吡格雷治疗的反应降低和心血管结局较差相关。
Clopidogrel therapy improves cardiovascular outcomes in patients with acute coronary syndromes and following percutaneous coronary intervention by inhibiting adenosine diphosphate (ADP)–dependent platelet activation. However, nonresponsiveness is widely recognized and is related to recurrent ischemic events. To identify gene variants that influence clopidogrel response. In the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study (2006-2008), we administered clopidogrel for 7 days to 429 healthy Amish persons and measured response by ex vivo platelet aggregometry. A genome-wide association study was performed followed by genotyping the loss-of-function cytochrome P450 (CYP) 2C19*2 variant (rs4244285). Findings in the PAPI Study were extended by examining the relation of CYP2C19*2 genotype to platelet function and cardiovascular outcomes in an independent sample of 227 patients undergoing percutaneous coronary intervention. ADP-stimulated platelet aggregation in response to clopidogrel treatment and cardiovascular events. Platelet response to clopidogrel was highly heritable (h=0.73; P<.001). Thirteen single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster were associated with diminished clopidogrel response, with a high degree of statistical significance (P=1.5 × 10−13 for rs12777823, additive model). The rs12777823 polymorphism was in strong linkage disequilibrium with the CYP2C19*2 variant, and was associated with diminished clopidogrel response, accounting for 12% of the variation in platelet aggregation to ADP (P=4.3 × 10−11). The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention (P=.02). Furthermore, patients with the CYP2C19*2 variant were more likely (20.9% vs 10.0%) to have a cardiovascular ischemic event or death during 1 year of follow-up (hazard ratio, 2.42; 95% confidence interval, 1.18-4.99; P=.02). CYP2C19*2 genotype was associated with diminished platelet response to clopidogrel treatment and poorer cardiovascular outcomes.
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影响因子：
2.8
作者：
Frere, Corinne;Cuisset, Thomas;Alessi, Marie-Christine
通讯作者：
Alessi, Marie-Christine
影响因子：
168.9
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Collet, Jean-Philippe;Hulot, Jean-Sebastien;Montalescot, Gilles
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Montalescot, Gilles
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Angiolillo, Dominick J.;Fernandez-Ortiz, Antonio;Costa, Marco A.
通讯作者：
Costa, Marco A.
影响因子：
20.3
作者：
Hulot, Jean-Sebastien;Bura, Alessandra;Gaussem, Pascale
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Gaussem, Pascale