细胞色素P450 2C19、对氧磷酶1基因多态性与氯吡格雷抵抗的关联性研究
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摘要
目的观察细胞色素P450 2C19基因(CYP2C19)*2/*3位点及对氧磷酶1基因(PON1) Q192R位点多态性与急性冠状动脉综合征患者氯吡格雷抵抗的相关性。方法回顾性收集258例急性冠状动脉综合征患者的临床资料,以服用常规剂量氯吡格雷5 d后血小板聚集率(PAG)作为评价指标,PAG> 50%定义为氯吡格雷抵抗,≤50%定义为氯吡格雷敏感。分析比较不同基因型氯吡格雷抵抗情况,Logistic回归筛选出可能影响氯吡格雷疗效的危险因素。结果氯吡格雷敏感组和抵抗组的血小板聚集率分别为(29. 53±11. 42)%和(66. 39±9. 52)%(P <0. 001),其他临床指标组间差异无统计学意义。CYP2C19快代谢型的血小板聚集率为(36. 60±18. 42)%,显著低于CYP2C19中间代谢型的(44. 64±21. 80)%(P <0. 01)和慢代谢型的(51. 89±17. 75)%(P <0. 001)。CYP2C19快代谢型、中间代谢型和慢代谢型的氯吡格雷抵抗发生率分别为22. 1%,39. 1%,56. 7%(P <0. 001)。PON1基因型组间血小板聚集率和氯吡格雷抵抗发生率差异均无统计学意义(均P> 0. 05)。Logistic回归提示CYP2C19(P <0. 01,OR=2. 687,95%CI:1. 514～4. 770)及PON1 (P <0. 05,OR=1. 928,95%CI:1. 051～3. 535)均为影响氯吡格雷疗效的危险因素。结论 CYP2C19*2/*3及PON1 Q192R基因多态性与急性冠状动脉综合征患者发生氯吡格雷抵抗具有相关性。
Objective To investigate the association between clopidogrel resistance and cytochrome P450 2C19( CYP2C19) * 2/* 3 and paraoxonase 1( PON1) Q1921 R gene polymorphisms in patients with acute coronary syndrome. Methods Clinical data of 258 patients with acute coronary syndrome was collected. The platelet aggregation rate( PAG)induced by ADP was used as the evaluation index after taking clopidogrel continuously for 5 d. PAG > 50% was defined as clopidogrel resistance,and ≤ 50% was defined as clopidogrel sensitivity. Comparisons of clopidogrel resistance in different genotypes were analyized,and logistic regression was used to screen the risk factors that might affect the efficacy of clopidogrel. Results PAG in clopidogrel sensitive group and resistance group were( 29. 53 ± 11. 42) % and( 66. 39 ± 9. 52) %( P <0. 001). There was no significant difference in other clinical indicators.The PAG of CYP2C19 extensive metabolizers( EM) was( 36. 60 ± 18. 42) %,which was significantly lower than that of CYP2C19 intermediate metabolizers [IM,( 44. 64 ± 21. 80) %, P < 0. 01] and poor metabolizers [PM,( 51. 89 ± 17. 75) %,P < 0. 001]. The incidences of clopidogrel resistance in CYP2C19 EM,IM and PM were22. 1%,39. 1% and 56. 7%( P < 0. 001). There was no significant difference in PAG and clopidogrel resistance among PON1 genotypes( P > 0. 05). In addition,Logistic regression indicated that CYP2C19( P < 0. 01,OR = 2. 687,95% CI: 1. 514-4. 770) and PON1( P < 0. 05,OR = 1. 928,95% CI: 1. 051-3. 535) were risk factors for clopidogrel resistance. Conclusion CYP2C19 * 2/* 3 and PON1Q192R gene polymorphisms are associated with clopidogrel resistance in patients with acute coronary syndrome.
Objective To investigate the association between clopidogrel resistance and cytochrome P450 2C19( CYP2C19) * 2/* 3 and paraoxonase 1( PON1) Q1921 R gene polymorphisms in patients with acute coronary syndrome. Methods Clinical data of 258 patients with acute coronary syndrome was collected. The platelet aggregation rate( PAG)induced by ADP was used as the evaluation index after taking clopidogrel continuously for 5 d. PAG > 50% was defined as clopidogrel resistance,and ≤ 50% was defined as clopidogrel sensitivity. Comparisons of clopidogrel resistance in different genotypes were analyized,and logistic regression was used to screen the risk factors that might affect the efficacy of clopidogrel. Results PAG in clopidogrel sensitive group and resistance group were( 29. 53 ± 11. 42) % and( 66. 39 ± 9. 52) %( P <0. 001). There was no significant difference in other clinical indicators.The PAG of CYP2C19 extensive metabolizers( EM) was( 36. 60 ± 18. 42) %,which was significantly lower than that of CYP2C19 intermediate metabolizers [IM,( 44. 64 ± 21. 80) %, P < 0. 01] and poor metabolizers [PM,( 51. 89 ± 17. 75) %,P < 0. 001]. The incidences of clopidogrel resistance in CYP2C19 EM,IM and PM were22. 1%,39. 1% and 56. 7%( P < 0. 001). There was no significant difference in PAG and clopidogrel resistance among PON1 genotypes( P > 0. 05). In addition,Logistic regression indicated that CYP2C19( P < 0. 01,OR = 2. 687,95% CI: 1. 514-4. 770) and PON1( P < 0. 05,OR = 1. 928,95% CI: 1. 051-3. 535) were risk factors for clopidogrel resistance. Conclusion CYP2C19 * 2/* 3 and PON1Q192R gene polymorphisms are associated with clopidogrel resistance in patients with acute coronary syndrome.
引文
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[9]刘涛,李妍,尹涛,等. CYP2C19基因多态性与冠心病危险因素对氯吡格雷抵抗的影响[J].现代生物医学进展,2012,12(7):1265-1269.
[10]XIE H G,ZOU J J,HU Z Y,et al. Individual variability in the disposition of and response to clopidogrel:Pharmacogenomics and beyond[J]. Pharmacol Therapeut,2011,129(3):267-289.
[11]NAKATA T,MIYAHARA M,NAKATANI K,et al. Relationship between CYP2C19 loss-of-function polymorphism and platelet reactivities with clopidogrel treatment in Japanese patients undergoing coronary stent implantation[J]. Circ J,2013,77(6):1436-1444.
[12]GUO Y M,ZHAO Z C,ZHANG L,et al. CYP2C19 polymorphisms in acute coronary syndrome patients undergoing clopidogrel therapy in Zhengzhou population[J]. Genet Mol Res,2016,15(2):8012.
[13]DONG P,YANG X,BIAN S. Genetic polymorphism of CYP2C19and inhibitory effects of ticagrelor and clopidogrel towards postpercutaneous coronary intervention(PCI)platelet aggregation in patients with acute coronary syndromes[J/OL]. Med Sci Monit,2016,22:4929-4936. 2016-12-15[2018-05-22]. https://www. ncbi. nlm. nih. gov/pmc/articles/PMC5181574/.
[14]ZHUO Z L,XIAN H P,LONG Y,et al. Association between CYP2C19 and ABCB1 polymorphisms and clopidogrel resistance in clopidogrel-treated Chinese patients[J]. Anatol J Cardiol,2018,19(2):AAC. 02365-17.
[15]YIN T,MIYATA T. Pharmacogenomics of clopidogrel:Evidence and perspectives[J]. Thromb Res,2011,128(4):307-316.
[2]SUGUNARAJ J P,PALANISWAMY C,SELVARAJ D R,et al.Clopidogrel resistance[J]. Anadolu Kardiyol Der,2010,9(3):210-215.
[3]GEIGER J,BRICH J,HONIGLIEDL P,et al. Specific impairment of human platelet P2Y(AC)ADP receptor-mediated signaling by the antiplatelet drug clopidogrel[J]. Arterioscl Throm Vas,1999,19(8):2007-2011.
[4]BONELLO L,TANTRY U S,MARCUCCI R,et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate[J]. J Am Coll Cardiol,2010,56(12):919-933.
[5]TANTRY U S,BONELLO L,ARADI D,et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding[J]. J Am Coll Cardiol,2013,62(24):2261-2273.
[6]GEISLER T,GRA D,BIGALKE B,et al. The residual platelet aggregation after deployment of intracoronary stent(PREDICT)score[J]. J Thromb Haemost,2010,6(1):54-61.
[7]FRERE C,CUISSET T,QUILICI J,et al. ADP-induced platelet aggregation and platelet reactivity index VASP are good predictive markers for clinical outcomes in non-ST elevation acute coronary syndrome[J]. Thromb Haemostasis,2007,98(4):838-843.
[8]FEHER G,KOLTAI K,ALKONYI B,et al. Clopidogrel resistance:role of body mass and concomitant medications[J]. Digest Cor Med J,2007,120(2):188-192.
[9]刘涛,李妍,尹涛,等. CYP2C19基因多态性与冠心病危险因素对氯吡格雷抵抗的影响[J].现代生物医学进展,2012,12(7):1265-1269.
[10]XIE H G,ZOU J J,HU Z Y,et al. Individual variability in the disposition of and response to clopidogrel:Pharmacogenomics and beyond[J]. Pharmacol Therapeut,2011,129(3):267-289.
[11]NAKATA T,MIYAHARA M,NAKATANI K,et al. Relationship between CYP2C19 loss-of-function polymorphism and platelet reactivities with clopidogrel treatment in Japanese patients undergoing coronary stent implantation[J]. Circ J,2013,77(6):1436-1444.
[12]GUO Y M,ZHAO Z C,ZHANG L,et al. CYP2C19 polymorphisms in acute coronary syndrome patients undergoing clopidogrel therapy in Zhengzhou population[J]. Genet Mol Res,2016,15(2):8012.
[13]DONG P,YANG X,BIAN S. Genetic polymorphism of CYP2C19and inhibitory effects of ticagrelor and clopidogrel towards postpercutaneous coronary intervention(PCI)platelet aggregation in patients with acute coronary syndromes[J/OL]. Med Sci Monit,2016,22:4929-4936. 2016-12-15[2018-05-22]. https://www. ncbi. nlm. nih. gov/pmc/articles/PMC5181574/.
[14]ZHUO Z L,XIAN H P,LONG Y,et al. Association between CYP2C19 and ABCB1 polymorphisms and clopidogrel resistance in clopidogrel-treated Chinese patients[J]. Anatol J Cardiol,2018,19(2):AAC. 02365-17.
[15]YIN T,MIYATA T. Pharmacogenomics of clopidogrel:Evidence and perspectives[J]. Thromb Res,2011,128(4):307-316.