CYP2C19 基因多态性与首发缺血性卒中氯吡格雷二级预防复发风险的关联研究

doi:10.3969/j.issn.1673-5765.2018.09.005

摘要/Abstract

摘要：

目的探讨CYP2C19基因多态性与规律服用氯吡格雷预防缺血性卒中二级复发风险之间的关系。

方法入组首次缺血性卒中的326例汉族患者，采用DNA微阵列芯片法检测CYP2C19基因多态性，随访患者缺血性卒中复发情况，分析规律服用氯吡格雷的患者卒中复发与CYP2C19基因多态性的关系。

结果对入组患者经过1～37个月[平均（14.44±5.07）个月]的随访，共139例规律服用氯吡格雷，其中29（20.86%）例出现卒中复发。中代谢型和慢代谢型患者的复发风险较快代谢型升高，比值比（odds ratio，OR）分别为3.05[95%可信区间（confidence interval，CI）1.11～8.43，P=0.025]和9.17（[ 95%CI 2.39～35.16，P <0.001]。携带*2（G681A）A等位基因患者的卒中复发风险是携带G 等位基因患者的 2.63倍（P <0.001）。携带*2突变杂合子和纯合子患者卒中复发风险分别是野生型的2.82倍（P =0.026）和9.69倍（P <0.001）。携带有1个失功能（loss of function，LOF）等位基因者卒中复发的风险是未携带者的3.02倍，（95％CI 1.13～8.05，P =0.030），携带2个LOF等位基因者卒中复发的风险是未携带者的 11.01倍（95％CI 2.67～45.24，P <0.001）。多因素Logistic回归分析提示携带LOF等位基因是卒中复发的独立危险因素。

结论规律服用氯吡格雷进行二级预防的首发缺血性卒中患者，中慢代谢型患者的卒中复发风险较快代谢型升高，携带CYP2C19 LOF等位基因是首发缺血性卒中患者卒中复发的独立危险因素。

文章导读： 本研究显示，在校正其他因素后，携带CYP2C19 失功能等位基因是规律服用氯吡格雷的首次缺血性卒中患者缺血性卒中复发的危险因素。

关键词: 基因多态性; 氯吡格雷; 首发缺血性卒中; 复发

Abstract:

Objective To investigate the association of CYP2C19 gene polymorphism with the risk of recurrent stroke in first-ever ischemic stroke (FIS) patients with clopidogrel for secondary prevention. Methods A total of 326 FIS patients who took Clopidogrel regularly were enrolled in this study, and recurrent stroke of all patients were recorded by follow-up. The CYP2C19 gene polymorphism were detected using DNA microarray method. The correlation between CYP2C19 gene polymorphism and stroke recurrence in patients taking Clopidogrel regularly was analyzed. Results After a mean follow-up period of (14.44±5.07) months, there were 139 patients who took Clopidogrel regularly, and 29 ones of which occurred recurrent stroke. Patients of poor metabolizer (PM) and intermediate metabolizer (IM) had higher risk of stroke recurrence comparing with patients of extensive metabolize (EM), and the odds ratio (OR) were 3.05 [95% confidence interval (CI) 1.11- 8.43, P =0.025] and 9.17 (95%CI 2.39-35.16, P <0.001), respectively. The recurrence risk of *2 (G681A ) A allele carriers was 2.63 times that of G allele carriers (P <0.001). The recurrence rate of stroke in patients carrying heterozygous and homozygous *2 allele mutant were 2.82 times (P =0.026) and 9.69 times (P <0.001) that of patients with wild-type genes. The recurrence rate in patients with one loss-of-function (LOF) allele was 3.02 times that of patients without mutant gene (95%CI 1.13-8.05,P =0.030), and this recurrence rate in patients with two LOF alleles was 11.01 times that of patients without mutant gene (95%CI 2.67-45.24, P <0.001). Multifactor logistic regression analysis result indicated carrying LOF allele was an independent risk factor of stroke recurrence. Conclusion For FIS patients taking Clopidogrel regularly for secondary prevention, IM and PM patients had higher risk of recurrent stroke comparing with EM ones. Carrying CYP2C19 LOF allele is an independent risk factor of stroke recurrence in FIS patients.

Key words: Gene polymorphism; Clopidogrel; First-ever ischemic stroke; Recurrence

曾涛, 肖旋浩, 徐邦牢, 雷秀霞, 李泽, 周进, 黄翚, 潘小平. CYP2C19 基因多态性与首发缺血性卒中氯吡格雷二级预防复发风险的关联研究[J]. 中国卒中杂志, 2018, 13(09): 908-914.

ZENG Tao, XIAO Xuan-Hao, XU Bang-Lao, LEI Xiu-Xia, LI Ze, ZHOU Jin, HUANG Hui, PAN Xiao-Ping. Association of CYP2C19 Gene Polymorphisms with Risk of Recurrent Stroke in First-ever Ischemic Stroke Patients with Clopidogrel for Secondary Prevention[J]. Chinese Journal of Stroke, 2018, 13(09): 908-914.

参考文献

[1] 肖旋浩，曾涛，雷秀霞，等. 广州地区老年汉族人群

CYP2C19 基因多态性分布及不同人群间的比较研

究[J]. 中山大学学报（医学科学版），2017，38（2）：

307-314.

[2] MEGA J L，CLOSE S L，WIVIOTT S D.

Cytochrome P-450 Polymorphisms and Response to

Clopidogrel[J]. N Engl J Med，2009，360（4）：354-

362.

[3] ADAMS H J，BENDIXEN B H，KAPPELLE L

J，et al. Classification of subtype of acute ischemic

stroke. Definitions for use in a multicenter clinical

trial. TOAST. Trial of Org 10172 in Acute Stroke

Treatment[J]. Stroke，1993，24（1）：35-41.

[4] 中华医学会神经病学分会，中华医学会神经病学分

会脑血管病学组. 中国急性缺血性脑卒中诊治指南

2014[J]. 中华神经科杂志，2014，48（4）：246-257.

[5] BAUER T，BOUMAN H J，VAN WERKUM J

W，et al. Impact of CYP2C19 variant genotypes

on clinical efficacy of antiplatelet treatment with

clopidogrel：systematic review and meta-analysis[J/

OL]. BMJ，2011，343（aug04 1）：d4588. https：//

dx.doi.org/10.1136%2Fbmj.d4588.

[6] SUN W，LI Y，LI J，et al. Variant recurrent risk

among stroke patients with different CYP2C19

phenotypes and treated with clopidogrel[J]. Platelets，

2015，26（6）：558-562.

[7] FANG L，ZHAO Y，WANG N，et al. Association

of CYP2C19 gene polymorphisms with long-term

recurrent risk of ischemic stroke among ethnic Han

Chinese from Fujian[J]. Zhonghua Yi X [8] WANG Y，ZHAO X，LIN J，et al. Association

Between CYP2C19 Loss-of-Function Allele Status

and Efficacy of Clopidogrel for Risk Reduction

Among Patients With Minor Stroke or Transient

Ischemic Attack[J]. JAMA，2016，316（1）：70-78.

[9] JIA D M，CHEN Z B，ZHANG M J，et al. CYP2C19

polymorphisms and antiplatelet effects of clopidogrel

in acute ischemic stroke in China[J]. Stroke，2013，

44（6）：1717-1719.

[10] QIU L N，SUN Y，WANG L，et al. Influence of

CYP2C19 polymorphisms on platelet reactivity and

clinical outcomes in ischemic stroke patients treated

with clopidogrel[J/OL]. Eur J Pharmacol，2015，747：

29-35. https：//doi.org/10.1016/j.ejphar.2014.11.037.

[11] TOPÇUOGLU M A，ARSAVA E M，AY H.

Antiplatelet resistance in stroke[J]. Expert Review of

Neurotherapeutics，2014，11（2）：251-263.

[12] HU L，DAI D，HU G，et al. Genetic polymorphisms

and novel allelic variants of CYP2C19 in the Chinese

Han population[J]. Pharmacogenomics，2012，13

（14）：1571-1581.

[13] ROBERTS J D，WELLS G A，LE MAY M R，et

al. Point-of-care genetic testing for personalisation

of antiplatelet treatment（RAPID GENE）：a

prospective，randomised，proof-of-concept trial[J].

Lancet，2012，379（9827）：1705-1711.

[14] CAYLA G，CUISSET T，SILVAIN J，et al. Platelet

function monitoring to adjust antiplatelet therapy

in elderly patients stented for an acute coronary

syndrome（ANTARCTIC）：an open-label，blindedendpoint，

randomised controlled superiority trial[J].

Lancet，2016，388（10055）：2015-2022.

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