广东佛山地区人群CYP2C19基因多态性及氯吡格雷药效反应的影响因素分析
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摘要
目的探讨佛山地区人群依赖细胞色素P450的加单氧酶系(CYP2C19)基因多态性及对该地区冠心病患者氯吡格雷药效反应的影响因素分析。方法选取2016年8月至2018年2月在我院住院的冠心病患者375例,均连续服用氯吡格雷75 mg/d 5天以上者,进行CYP2C19基因型及血小板聚集功能检测,根据血小板聚集功能检测来判断氯吡格雷药效反应性,>50%为氯吡格雷抵抗。统计CYP2C19基因型及等位基因的分布规律,比较氯吡格雷抵抗及氯吡格雷反应组的基因分布和基本资料,并行Logistic多因素分析。结果 375名冠心病患者中突变纯合型占12.27%,突变杂合型占45.60%,野生型占42.13%;氯吡格雷抵抗组和氯吡格雷反应组在基因表型和等位基因频率分布上有明显差异(P<0. 05),突变纯合型在氯吡格雷抵抗组显著高于氯吡格雷抵反应组;氯吡格雷抵抗组与氯吡格雷反应组的年龄、性别、糖尿病、高血压、高胆固醇血症、血小板计数、纤维蛋白原水平比较,差异无统计学意义(P>0.05),氯吡格雷抵抗组CYP2C19突变纯合和突变杂合型所占比例高于氯吡格雷反应组,差异有统计学意义(P<0.05);经Logistic分析,CYP2C19突变纯合型(OR=2.557)和突变杂合型(OR=2.027)为氯吡格雷抵抗的危险因素。结论佛山地区人群CYP2C19基因型与广东其它地区人群分布相似,突变纯合型和突变杂合型为佛山地区人群发生氯吡格雷抵抗的危险因素,应采取有效措施进行干预。
Objective To investigate the genetic polymorphisms of CYP2C19 gene and its effect on the response to clopidogrel in patients with coronary heart disease in Foshan area. Methods A total of375 patients with coronary heart disease who were admitted to the Foshan First People's Hospital from August2016 to February 2018 were enrolled. All patients who received clopidogrel 75 mg/d for more than 5 days were tested for CYP2C19 genotype and platelet aggregation test. The pharmacodynamic reactivity of clopidogrel was judged based on the results of platelet aggregation function test. If it is more than 50% determined as a clopidogrel resistance. The distribution patterns of CYP2C19 genotypes and alleles were statistically analyzed.The gene distribution and basic data of clopidogrel resistance and clopidogrel responders were compared,and logistic multivariate analysis was performed. Results Among 375 patients with coronary heart disease,the slow metabolic genotype accounted for 12.27%,the intermediate metabolic genotype for 45.60%,and the fast metabolizing genotype for 42.13%. There was a significant difference in gene phenotype and allele frequency distribution between clopidogrel resistance group and clopidogrel reaction group(P<0.05). Mutation homozygous type was significantly higher in clopidogrel resistance group than in reaction group. The levels of diabetes,hypertension,hypercholesterolemia,PLT and fibrinogen levels were no significant difference between the 2 groups(P>0.05). The proportion of slow metabolism and intermediate metabolic genotypes of CYP2C19 in clopidogrel resistant patients was higher than that in clopidogrel reaction patients,and the difference was statistically significant(P<0.05). Logistic analysis showed that CYP2C19 slow metabolism(OR=2.557) and intermediate metabolism(OR=2.027) genotype were risk factors for clopidogrel resistance.Conclusion The CYP2C19 genotype in Foshan population is similar to that in other parts of Guangdong. The slow metabolism and intermediate metabolic genotypes are risk factors for clopidogrel resistance in Foshan population. Effective measures should be taken to intervene.
Objective To investigate the genetic polymorphisms of CYP2C19 gene and its effect on the response to clopidogrel in patients with coronary heart disease in Foshan area. Methods A total of375 patients with coronary heart disease who were admitted to the Foshan First People's Hospital from August2016 to February 2018 were enrolled. All patients who received clopidogrel 75 mg/d for more than 5 days were tested for CYP2C19 genotype and platelet aggregation test. The pharmacodynamic reactivity of clopidogrel was judged based on the results of platelet aggregation function test. If it is more than 50% determined as a clopidogrel resistance. The distribution patterns of CYP2C19 genotypes and alleles were statistically analyzed.The gene distribution and basic data of clopidogrel resistance and clopidogrel responders were compared,and logistic multivariate analysis was performed. Results Among 375 patients with coronary heart disease,the slow metabolic genotype accounted for 12.27%,the intermediate metabolic genotype for 45.60%,and the fast metabolizing genotype for 42.13%. There was a significant difference in gene phenotype and allele frequency distribution between clopidogrel resistance group and clopidogrel reaction group(P<0.05). Mutation homozygous type was significantly higher in clopidogrel resistance group than in reaction group. The levels of diabetes,hypertension,hypercholesterolemia,PLT and fibrinogen levels were no significant difference between the 2 groups(P>0.05). The proportion of slow metabolism and intermediate metabolic genotypes of CYP2C19 in clopidogrel resistant patients was higher than that in clopidogrel reaction patients,and the difference was statistically significant(P<0.05). Logistic analysis showed that CYP2C19 slow metabolism(OR=2.557) and intermediate metabolism(OR=2.027) genotype were risk factors for clopidogrel resistance.Conclusion The CYP2C19 genotype in Foshan population is similar to that in other parts of Guangdong. The slow metabolism and intermediate metabolic genotypes are risk factors for clopidogrel resistance in Foshan population. Effective measures should be taken to intervene.
引文
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[9]Shumyantseva VV,Bulko T,Shich E,et al.Cytochrome p450 enzymes and electrochemistry:crosstalk with electrodes as redox partners and electron sources[J].Adv Exp Med Biol,2015,851(1):229-246.
[10]Juki?MM,Haslemo T,Molden E,et al.Impact of CYP2C19 genotype on escitalopram exposure and therapeutic failure:a retrospective study based on 2087 patients[J].Am J Psychiatry,2018,175(5):463-470.
[11]Garimella T,Tao X,Sims K,et al.Effects of a fixeddose co-formulation of daclatasvir,asunaprevir,and beclabuvir on the pharmacokinetics of a cocktail of cytochrome P450 and drug transporter substrates in healthy subjects[J].Drug R D,2018,18(1):55-65.
[12]Tajima H,Izumi T,Miyachi S,et al.Association between CYP2C19 genotype and the additional effect of cilostazol to clopidogrel resistance in neuroendovascular therapy[J].Nagoya J Med Sci,2018,80(2):207-215.
[13]Zhong Z,Hou J,Zhang Q,et al.Effect of cytochrome P450 2C19 polymorphism on adverse cardiovascular events after drug-eluting stent implantation in a large Hakka population with acute coronary syndrome receiving clopidogrel in southern China[J].Eur J Clin Pharmacol,2018,74(4):423-431.
[14]Hassani IH,Hmimech W,Khorb NE,et al.A synergic effect between CYP2C19*2,CYP2C19*3 loss-offunction and CYP2C19*17 gain-of-function alleles is associated with clopidogrel resistance among moroccan acute coronary syndromes patients[J].BMC Res Notes,2018,11(1):46.
[15]Winter MP,Koziński M,Kubica J,et al.Personalized antiplatelet therapy with P2Y12 receptor inhibitors:benefits and pitfalls[J].Postepy Kardiol Interwencyjnej,2015,11(4):259-80.
[2]李桂梅,陈凤英,崔晓迎,等.蒙古族PCI病人CYP2C19基因多态性与氯吡格雷抵抗相关性研究[J].内蒙古医科大学学报,2017,39(2):128-132.
[3]尚红,王毓三,申子瑜.全国临床检验操作规程[M].第4版.北京:人民卫生出版社,2015:14.
[4]Sridharan K,Kataria R,Tolani D,et al.Evaluation of CYP2C19,P2Y12,and ABCB1 polymorphisms and phenotypic response to clopidogrel in healthy Indian adults[J].Indian J Pharmacol,2016,48(4):350-354.
[5]Ray S.Clopidogrel resistance:the way forward[J].Indian Heart J,2014,66(5):530-534.
[6]方伟祯,蔡振华.广州地区汉族人群CYP2C19基因多态性的分布[J].江苏医药,2017,43(21):1556-1558.
[7]刘秀卿,李卓成,李延武.CYP2C19基因多态性荧光定量PCR检测方法的建立[J].临床检验杂志,2016,34(2):95-99.
[8]华仙丽,梁爱芬,雷亚利,等.广东东莞地区心血管疾病患者CYP2C19基因多态性分析[J].国际检验医学杂志,2017,38(5):606-608.
[9]Shumyantseva VV,Bulko T,Shich E,et al.Cytochrome p450 enzymes and electrochemistry:crosstalk with electrodes as redox partners and electron sources[J].Adv Exp Med Biol,2015,851(1):229-246.
[10]Juki?MM,Haslemo T,Molden E,et al.Impact of CYP2C19 genotype on escitalopram exposure and therapeutic failure:a retrospective study based on 2087 patients[J].Am J Psychiatry,2018,175(5):463-470.
[11]Garimella T,Tao X,Sims K,et al.Effects of a fixeddose co-formulation of daclatasvir,asunaprevir,and beclabuvir on the pharmacokinetics of a cocktail of cytochrome P450 and drug transporter substrates in healthy subjects[J].Drug R D,2018,18(1):55-65.
[12]Tajima H,Izumi T,Miyachi S,et al.Association between CYP2C19 genotype and the additional effect of cilostazol to clopidogrel resistance in neuroendovascular therapy[J].Nagoya J Med Sci,2018,80(2):207-215.
[13]Zhong Z,Hou J,Zhang Q,et al.Effect of cytochrome P450 2C19 polymorphism on adverse cardiovascular events after drug-eluting stent implantation in a large Hakka population with acute coronary syndrome receiving clopidogrel in southern China[J].Eur J Clin Pharmacol,2018,74(4):423-431.
[14]Hassani IH,Hmimech W,Khorb NE,et al.A synergic effect between CYP2C19*2,CYP2C19*3 loss-offunction and CYP2C19*17 gain-of-function alleles is associated with clopidogrel resistance among moroccan acute coronary syndromes patients[J].BMC Res Notes,2018,11(1):46.
[15]Winter MP,Koziński M,Kubica J,et al.Personalized antiplatelet therapy with P2Y12 receptor inhibitors:benefits and pitfalls[J].Postepy Kardiol Interwencyjnej,2015,11(4):259-80.