Correlation between the Genetic Polymorphism of CYP2C19*2, *3 and the Clinical Efficacy of Clopidogrel: A Systematic Review△_Chinese Journal of Evidence-Based Medicine

Authors：

YANG Liping ¹ , XIE Jing ^1,2 , LIU Yao ¹ ,  HU Xin ¹

1. Department of Pharmacy, Beijing Hospital, Ministry of Public Health, Beijing 100730, China; 2. College of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China;

Corresponding author：

HU Xin, Email: huxinbjyy@126.com

Keywords：

Clopidogrel; Cardiovascular disease; CYP2C19; Genetic polymorphisms; Meta-analysis; Safe medication

DOI：

10.7507/1672-2531.20120166

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective 　To systematically evaluate anti-platelet effect of clopidogrel influenced by CYP2C192,3 polymorphism in patients with cardiovascular diseases, in order to provide references for its safe medication.
Methods 　Literature was retrieved in electronic databases covering EMbase, PubMed, The Cochrane Library, CBM and CNKI from establishment dates to November, 2011. Observational studies and clinical trials were included, cross-checked, assessed and pooled for meta-analysis. meta-analysis was performed using the software RevMan 5.1.
Results 　A total of 13 articles including 14 trials (n=36 855) were included. The results of meta-analysis showed that: a) there was no significant difference in the incidences of cardiovascular events between CYP2C192,3 carriers and CYP2C191 carriers; b) the risk of stent thrombosis in CYP2C192,3 carriers was significantly higher than that in CYP2C191 carriers (P lt;0.000 1), and the relative risk of CYP2C192,3 carriers increased 92% within one month (P lt;0.000 1); c) as for bleeding events, there were no significant differences between CYP2C192,3 carriers and CYP2C191 carriers.
Conclusion 　Compared with CYP2C191 carriers, CYP2C192,3 carriers have a higher risk of stent thrombosis in clopidogrel-treated patients, but there are few differences in cardiovascular and bleeding events between the two carriers. Therefore, CYP2C192,3 carriers with cardiovascular diseases and ready to receive PCT are suggested to pay more attention to stent thrombosis when using clopidogrel. We propose that patients with cardiovascular diseases and ready to receive PCT should have CYP2C19 tests to determine the use of antiplatelet drug (clopidogrel) to avoid thrombus.

Citation： YANG Liping,XIE Jing,LIU Yao,HU Xin. Correlation between the Genetic Polymorphism of CYP2C19*2, *3 and the Clinical Efficacy of Clopidogrel: A Systematic Review△. Chinese Journal of Evidence-Based Medicine, 2012, 12(9): 1063-1070. doi: 10.7507/1672-2531.20120166 Copy

1. Uchiyama S. Clopidogrel Resistance: Identifying and overcoming a barrier to effective antiplatelet treatment. Cardiovascular Therapeutics, 2011, 29(6): e100-e11.

2. Plosker GL, Lyseng-Williamson KA. Clopidogrel: A review of its use in the prevention of thrombosis. Drugs, 2007, 67(4): 613-646.

3. Singh M, Thapa B, Arora R. Clopidogrel pharmacogenetics and its clinical implications. American Journal of Therapeutics, 2010, 17(3): e66-e73.

4. Sofi F, Marcucci R, Gori AM, et al. Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost, 2010, 103(4): 841-848.

5. Gurbel PA, Tantry US. Drug Insight: Clopidogrel nonresponsiveness. Nature Clinical Practice Cardiovascular Medicine, 2006, 3(7): 387-395.

6. van Werkum JW, Heestermans AACM, Deneer VHM, et al. Clopidogrel resistance: Fact and fiction. Future Cardiology, 2006, 2(2): 215-228.

7. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: A review of the evidence. Journal of the American College of Cardiology, 2005, 45(8): 1157-1164.

8. Park KW, Park JJ, Jeon KH, et al. Enhanced clopidogrel responsiveness in smokers, nullsmokers’ paradoxnull is dependent on cytochrome P450 CYP1A2 status. Journal of the American College of Cardiology, 2010, 56(13): B1.

9. Bates ER, Lau WC, Angiolillo DJ. Clopidogrel-drug interactions. Journal of the American College of Cardiology, 2011, 57(11): 1251-1263.

10. Ford NF. Clopidogrel resistance: Pharmacokinetic or pharmacogenetic? Journal of Clinical Pharmacology, 2009, 49(5): 506-512.

11. Achar S. Pharmacokinetics, drug metabolism, and safety of prasugrel and clopidogrel. Postgraduate Medicine, 2011, 123(1): 73-79.

12. Kim KA, Park PW, Hong SJ, et al. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther, 2008, 84(2): 236-242.

13. Pettersen AA, Arnesen H, Opstad TB, et al. The influence of CYP 2C19*2 polymorphism on platelet function testing during single antiplatelet treatment with clopidogrel. Thromb J, 2011, 94.

14. Tantry US, Bliden KP, Wei C, et al. First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: The ONSET/OFFSET and RESPOND genotype studies. Circulation: Cardiovascular Genetics, 2010, 3(6): 556-566.

15. Frere C, Cuisset T, Gaborit B, et al. The CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-ST acute coronary syndrome. J Thromb Haemost, 2009, 7(8): 1409-1411.

16. Scott SA, Sangkuhl K, Gardner EE, et al. Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clinical Pharmacology and Therapeutics, 2011, 90(2): 328-332.

17. Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther, 2011, 89(5): 662-673.

18. Swen JJ, Wilting I, de Goede AL, et al. Pharmacogenetics: from bench to byte. Clin Pharmacol Ther, 2008, 83(5): 781-787.

19. Pare G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med, 2010, 363(18): 1704-1714.

20. Administration. FaD. FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug.: U.S. Food and Drug Administration; 2010 [cited 2011 Nov17]; [4 screen]. Available from: http: //www.fda.gov/Drugs/DrugSafety/.

21. Bouman HJ, Schomig E, van Werkum JW, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nature medicine, 2011, 17(1): 110-116.

22. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet, 2009, 373(9660): 309-317.

23. Giusti B, Gori AM, Marcucci R, et al. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am J Cardiol, 2009, 103(6): 806-811.

24. Malek LA, Kisiel B, Spiewak M, et al. Coexisting polymorphisms of P2Y12 and CYP2C19 genes as a risk factor for persistent platelet activation with clopidogrel. Circ J, 2008, 72(7): 1165-1169.

25. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med, 2009, 360(4): 354-362.

26. Sawada T, Shinke T, Shite J, et al. Impact of cytochrome P450 2C19*2 polymorphism on intra-stent thrombus after drug-eluting stent implantation in Japanese patients receiving clopidogrel. Circ J, 2010, 75(1): 99-105.

27. Sibbing D, Stegherr J, Latz W, et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J, 2009, 30(8): 916-922.

28. Sibbing D, Koch W, Massberg S, et al. No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Eur Heart J, 2011, 32(13): 1605-1613.

29. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med, 2009, 360(4): 363-375.

30. Tiroch KA, Sibbing D, Koch W, et al. Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am Heart J, 2010, 160(3): 506-512.

31. Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet, 2010, 376(9749): 1320-1328.

32. Yamamoto K, Hokimoto S, Chitose T, et al. Impact of CYP2C19 polymorphism on residual platelet reactivity in patients with coronary heart disease during antiplatelet therapy. J Cardiol, 2011, 57(2): 194-201.

33. Karunakaran A, Judge H, Morton A, et al. Cytochrome P450 2C19 loss-of-function genetic variants but not paraoxonase-1 activity modulate P2Y12 blockade in response to clopidogrel therapy. Journal of the American College of Cardiology, 2011, 58(20): B45.

34. Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug metabolism and disposition: the biological fate of chemicals, 2010, 38(1): 92-99.

35. Simon T, Bhatt DL, Bergougnan L, et al. Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects. Clinical Pharmacology and Therapeutics, 2011, 90(2): 287-295.

36. Harmsze AM, Van Werkum JW, Ten Berg JM, et al. Effect of genetic variants on the effectiveness of clopidogrel. Pharmaceutisch Weekblad, 2011, 146(20): 79-84.

37. Mo SL, Liu YH, Duan W, et al. Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6. Current Drug Metabolism, 2009, 10(7): 730-753.

38. PharmGKB. Variant in CYP2C19. Stanford University; 2012 [cited 2012 April. 19]; [2 screen]. Available from: https: //www.pharmgkb.org.

39. Beitelshees AL, Horenstein RB, Vesely MR, et al. Pharmacogenetics and clopidogrel response in patients undergoing percutaneous coronary interventions. Clinical Pharmacology and Therapeutics, 2011, 89(3): 455-459.

40. Luo Y, Zhao YT, Verdo A, et al. Relationship between cytochrome P450 2C19*2 polymorphism and stent thrombosis following percutaneous coronary intervention in Chinese patients receiving clopidogrel. Journal of International Medical Research, 2011, 39(5): 2012-2019.

41. Zabalza M, Subirana I, Sala J, et al. Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel. Heart, 2011, 98(2): 100-108.

42. Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA, 2010, 304(16): 1821-1830.

43. Bauer T, Bouman HJ, van Werkum JW, et al. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ, 2011, 343d4588.

1. Uchiyama S. Clopidogrel Resistance: Identifying and overcoming a barrier to effective antiplatelet treatment. Cardiovascular Therapeutics, 2011, 29(6): e100-e11.

2. Plosker GL, Lyseng-Williamson KA. Clopidogrel: A review of its use in the prevention of thrombosis. Drugs, 2007, 67(4): 613-646.

3. Singh M, Thapa B, Arora R. Clopidogrel pharmacogenetics and its clinical implications. American Journal of Therapeutics, 2010, 17(3): e66-e73.

4. Sofi F, Marcucci R, Gori AM, et al. Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost, 2010, 103(4): 841-848.

5. Gurbel PA, Tantry US. Drug Insight: Clopidogrel nonresponsiveness. Nature Clinical Practice Cardiovascular Medicine, 2006, 3(7): 387-395.

6. van Werkum JW, Heestermans AACM, Deneer VHM, et al. Clopidogrel resistance: Fact and fiction. Future Cardiology, 2006, 2(2): 215-228.

7. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: A review of the evidence. Journal of the American College of Cardiology, 2005, 45(8): 1157-1164.

8. Park KW, Park JJ, Jeon KH, et al. Enhanced clopidogrel responsiveness in smokers, nullsmokers’ paradoxnull is dependent on cytochrome P450 CYP1A2 status. Journal of the American College of Cardiology, 2010, 56(13): B1.

9. Bates ER, Lau WC, Angiolillo DJ. Clopidogrel-drug interactions. Journal of the American College of Cardiology, 2011, 57(11): 1251-1263.

10. Ford NF. Clopidogrel resistance: Pharmacokinetic or pharmacogenetic? Journal of Clinical Pharmacology, 2009, 49(5): 506-512.

11. Achar S. Pharmacokinetics, drug metabolism, and safety of prasugrel and clopidogrel. Postgraduate Medicine, 2011, 123(1): 73-79.

12. Kim KA, Park PW, Hong SJ, et al. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther, 2008, 84(2): 236-242.

13. Pettersen AA, Arnesen H, Opstad TB, et al. The influence of CYP 2C19*2 polymorphism on platelet function testing during single antiplatelet treatment with clopidogrel. Thromb J, 2011, 94.

14. Tantry US, Bliden KP, Wei C, et al. First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: The ONSET/OFFSET and RESPOND genotype studies. Circulation: Cardiovascular Genetics, 2010, 3(6): 556-566.

15. Frere C, Cuisset T, Gaborit B, et al. The CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-ST acute coronary syndrome. J Thromb Haemost, 2009, 7(8): 1409-1411.

16. Scott SA, Sangkuhl K, Gardner EE, et al. Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clinical Pharmacology and Therapeutics, 2011, 90(2): 328-332.

17. Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther, 2011, 89(5): 662-673.

18. Swen JJ, Wilting I, de Goede AL, et al. Pharmacogenetics: from bench to byte. Clin Pharmacol Ther, 2008, 83(5): 781-787.

19. Pare G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med, 2010, 363(18): 1704-1714.

20. Administration. FaD. FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug.: U.S. Food and Drug Administration; 2010 [cited 2011 Nov17]; [4 screen]. Available from: http: //www.fda.gov/Drugs/DrugSafety/.

21. Bouman HJ, Schomig E, van Werkum JW, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nature medicine, 2011, 17(1): 110-116.

22. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet, 2009, 373(9660): 309-317.

23. Giusti B, Gori AM, Marcucci R, et al. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am J Cardiol, 2009, 103(6): 806-811.

24. Malek LA, Kisiel B, Spiewak M, et al. Coexisting polymorphisms of P2Y12 and CYP2C19 genes as a risk factor for persistent platelet activation with clopidogrel. Circ J, 2008, 72(7): 1165-1169.

25. Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med, 2009, 360(4): 354-362.

26. Sawada T, Shinke T, Shite J, et al. Impact of cytochrome P450 2C19*2 polymorphism on intra-stent thrombus after drug-eluting stent implantation in Japanese patients receiving clopidogrel. Circ J, 2010, 75(1): 99-105.

27. Sibbing D, Stegherr J, Latz W, et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J, 2009, 30(8): 916-922.

28. Sibbing D, Koch W, Massberg S, et al. No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Eur Heart J, 2011, 32(13): 1605-1613.

29. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med, 2009, 360(4): 363-375.

30. Tiroch KA, Sibbing D, Koch W, et al. Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am Heart J, 2010, 160(3): 506-512.

31. Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet, 2010, 376(9749): 1320-1328.

32. Yamamoto K, Hokimoto S, Chitose T, et al. Impact of CYP2C19 polymorphism on residual platelet reactivity in patients with coronary heart disease during antiplatelet therapy. J Cardiol, 2011, 57(2): 194-201.

33. Karunakaran A, Judge H, Morton A, et al. Cytochrome P450 2C19 loss-of-function genetic variants but not paraoxonase-1 activity modulate P2Y12 blockade in response to clopidogrel therapy. Journal of the American College of Cardiology, 2011, 58(20): B45.

34. Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug metabolism and disposition: the biological fate of chemicals, 2010, 38(1): 92-99.

35. Simon T, Bhatt DL, Bergougnan L, et al. Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects. Clinical Pharmacology and Therapeutics, 2011, 90(2): 287-295.

36. Harmsze AM, Van Werkum JW, Ten Berg JM, et al. Effect of genetic variants on the effectiveness of clopidogrel. Pharmaceutisch Weekblad, 2011, 146(20): 79-84.

37. Mo SL, Liu YH, Duan W, et al. Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6. Current Drug Metabolism, 2009, 10(7): 730-753.

38. PharmGKB. Variant in CYP2C19. Stanford University; 2012 [cited 2012 April. 19]; [2 screen]. Available from: https: //www.pharmgkb.org.

39. Beitelshees AL, Horenstein RB, Vesely MR, et al. Pharmacogenetics and clopidogrel response in patients undergoing percutaneous coronary interventions. Clinical Pharmacology and Therapeutics, 2011, 89(3): 455-459.

40. Luo Y, Zhao YT, Verdo A, et al. Relationship between cytochrome P450 2C19*2 polymorphism and stent thrombosis following percutaneous coronary intervention in Chinese patients receiving clopidogrel. Journal of International Medical Research, 2011, 39(5): 2012-2019.

41. Zabalza M, Subirana I, Sala J, et al. Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel. Heart, 2011, 98(2): 100-108.

42. Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA, 2010, 304(16): 1821-1830.

43. Bauer T, Bouman HJ, van Werkum JW, et al. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ, 2011, 343d4588.

Previous Article
Survey on Gastroenterologists’ Evidence-Based Medicine Practice and Relevant Factor

Next Article
Correlation of Angiotensin-I Converting Enzyme Gene Insertion (I), Deletion (D) Polymorphism and Type 2 Diabetic Nephropathy: A Meta-Analysis

Chinese Journal of Evidence-Based Medicine

Correlation between the Genetic Polymorphism of CYP2C192, 3 and the Clinical Efficacy of Clopidogrel: A Systematic Review△

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content

1.	Uchiyama S. Clopidogrel Resistance: Identifying and overcoming a barrier to effective antiplatelet treatment. Cardiovascular Therapeutics, 2011, 29(6): e100-e11.
2.	Plosker GL, Lyseng-Williamson KA. Clopidogrel: A review of its use in the prevention of thrombosis. Drugs, 2007, 67(4): 613-646.
3.	Singh M, Thapa B, Arora R. Clopidogrel pharmacogenetics and its clinical implications. American Journal of Therapeutics, 2010, 17(3): e66-e73.
4.	Sofi F, Marcucci R, Gori AM, et al. Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost, 2010, 103(4): 841-848.
5.	Gurbel PA, Tantry US. Drug Insight: Clopidogrel nonresponsiveness. Nature Clinical Practice Cardiovascular Medicine, 2006, 3(7): 387-395.
6.	van Werkum JW, Heestermans AACM, Deneer VHM, et al. Clopidogrel resistance: Fact and fiction. Future Cardiology, 2006, 2(2): 215-228.
7.	Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: A review of the evidence. Journal of the American College of Cardiology, 2005, 45(8): 1157-1164.
8.	Park KW, Park JJ, Jeon KH, et al. Enhanced clopidogrel responsiveness in smokers, nullsmokers’ paradoxnull is dependent on cytochrome P450 CYP1A2 status. Journal of the American College of Cardiology, 2010, 56(13): B1.
9.	Bates ER, Lau WC, Angiolillo DJ. Clopidogrel-drug interactions. Journal of the American College of Cardiology, 2011, 57(11): 1251-1263.
10.	Ford NF. Clopidogrel resistance: Pharmacokinetic or pharmacogenetic? Journal of Clinical Pharmacology, 2009, 49(5): 506-512.
11.	Achar S. Pharmacokinetics, drug metabolism, and safety of prasugrel and clopidogrel. Postgraduate Medicine, 2011, 123(1): 73-79.
12.	Kim KA, Park PW, Hong SJ, et al. The effect of CYP2C19 polymorphism on the pharmacokinetics and pharmacodynamics of clopidogrel: a possible mechanism for clopidogrel resistance. Clin Pharmacol Ther, 2008, 84(2): 236-242.
13.	Pettersen AA, Arnesen H, Opstad TB, et al. The influence of CYP 2C19*2 polymorphism on platelet function testing during single antiplatelet treatment with clopidogrel. Thromb J, 2011, 94.
14.	Tantry US, Bliden KP, Wei C, et al. First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: The ONSET/OFFSET and RESPOND genotype studies. Circulation: Cardiovascular Genetics, 2010, 3(6): 556-566.
15.	Frere C, Cuisset T, Gaborit B, et al. The CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-ST acute coronary syndrome. J Thromb Haemost, 2009, 7(8): 1409-1411.
16.	Scott SA, Sangkuhl K, Gardner EE, et al. Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clinical Pharmacology and Therapeutics, 2011, 90(2): 328-332.
17.	Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther, 2011, 89(5): 662-673.
18.	Swen JJ, Wilting I, de Goede AL, et al. Pharmacogenetics: from bench to byte. Clin Pharmacol Ther, 2008, 83(5): 781-787.
19.	Pare G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med, 2010, 363(18): 1704-1714.
20.	Administration. FaD. FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug.: U.S. Food and Drug Administration; 2010 [cited 2011 Nov17]; [4 screen]. Available from: http: //www.fda.gov/Drugs/DrugSafety/.
21.	Bouman HJ, Schomig E, van Werkum JW, et al. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nature medicine, 2011, 17(1): 110-116.
22.	Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet, 2009, 373(9660): 309-317.
23.	Giusti B, Gori AM, Marcucci R, et al. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting coronary stent thrombosis. Am J Cardiol, 2009, 103(6): 806-811.
24.	Malek LA, Kisiel B, Spiewak M, et al. Coexisting polymorphisms of P2Y12 and CYP2C19 genes as a risk factor for persistent platelet activation with clopidogrel. Circ J, 2008, 72(7): 1165-1169.
25.	Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med, 2009, 360(4): 354-362.
26.	Sawada T, Shinke T, Shite J, et al. Impact of cytochrome P450 2C19*2 polymorphism on intra-stent thrombus after drug-eluting stent implantation in Japanese patients receiving clopidogrel. Circ J, 2010, 75(1): 99-105.
27.	Sibbing D, Stegherr J, Latz W, et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J, 2009, 30(8): 916-922.
28.	Sibbing D, Koch W, Massberg S, et al. No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting. Eur Heart J, 2011, 32(13): 1605-1613.
29.	Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med, 2009, 360(4): 363-375.
30.	Tiroch KA, Sibbing D, Koch W, et al. Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am Heart J, 2010, 160(3): 506-512.
31.	Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet, 2010, 376(9749): 1320-1328.
32.	Yamamoto K, Hokimoto S, Chitose T, et al. Impact of CYP2C19 polymorphism on residual platelet reactivity in patients with coronary heart disease during antiplatelet therapy. J Cardiol, 2011, 57(2): 194-201.
33.	Karunakaran A, Judge H, Morton A, et al. Cytochrome P450 2C19 loss-of-function genetic variants but not paraoxonase-1 activity modulate P2Y12 blockade in response to clopidogrel therapy. Journal of the American College of Cardiology, 2011, 58(20): B45.
34.	Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug metabolism and disposition: the biological fate of chemicals, 2010, 38(1): 92-99.
35.	Simon T, Bhatt DL, Bergougnan L, et al. Genetic polymorphisms and the impact of a higher clopidogrel dose regimen on active metabolite exposure and antiplatelet response in healthy subjects. Clinical Pharmacology and Therapeutics, 2011, 90(2): 287-295.
36.	Harmsze AM, Van Werkum JW, Ten Berg JM, et al. Effect of genetic variants on the effectiveness of clopidogrel. Pharmaceutisch Weekblad, 2011, 146(20): 79-84.
37.	Mo SL, Liu YH, Duan W, et al. Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6. Current Drug Metabolism, 2009, 10(7): 730-753.
38.	PharmGKB. Variant in CYP2C19. Stanford University; 2012 [cited 2012 April. 19]; [2 screen]. Available from: https: //www.pharmgkb.org.
39.	Beitelshees AL, Horenstein RB, Vesely MR, et al. Pharmacogenetics and clopidogrel response in patients undergoing percutaneous coronary interventions. Clinical Pharmacology and Therapeutics, 2011, 89(3): 455-459.
40.	Luo Y, Zhao YT, Verdo A, et al. Relationship between cytochrome P450 2C19*2 polymorphism and stent thrombosis following percutaneous coronary intervention in Chinese patients receiving clopidogrel. Journal of International Medical Research, 2011, 39(5): 2012-2019.
41.	Zabalza M, Subirana I, Sala J, et al. Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel. Heart, 2011, 98(2): 100-108.
42.	Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA, 2010, 304(16): 1821-1830.
43.	Bauer T, Bouman HJ, van Werkum JW, et al. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ, 2011, 343d4588.