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Identification of CYP2C19*4B: pharmacogenetic implications for drug metabolism including clopidogrel responsiveness

The Pharmacogenomics Journal volume 12, pages 297–305 (2012)Cite this article

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Abstract

CYP2C19 is a principal enzyme involved in the bioactivation of the antiplatelet prodrug clopidogrel and common CYP2C19 loss-of-function alleles are associated with adverse cardiovascular events. To assess the impact of the CYP2C19*17 increased activity allele in the Ashkenazi Jewish (AJ) and Sephardi Jewish (SJ) populations and to determine the frequencies of additional variant alleles, 250 AJ and 135 SJ individuals were genotyped for CYP2C19*2–*10, *12–*17, *22 and P-glycoprotein (ABCB1) c.3435C>T. Importantly, CYP2C19*4, a loss-of-function allele, was identified in linkage disequilibrium with *17. This novel haplotype, designated CYP2C19*4B, significantly alters the interpretation of CYP2C19 genotyping when testing *17. Moreover, genotyping CYP2C19*17 changed the frequency of extensive metabolizers from ∼70 to ∼40%, reclassifying ∼30% as ultrarapid metabolizers. Combining CYP2C19 and ABCB1 identified ∼1 in 3 AJ and ∼1 in 2 SJ individuals at increased risk for adverse responses to clopidogrel. These data underscore the importance of including *4B and *17 when clinically genotyping CYP2C19.

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References

  1. Ingelman-Sundberg M . Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms. Naunyn Schmiedebergs Arch Pharmacol 2004; 369: 89–104.

    Article  CAS  PubMed  Google Scholar 

  2. Ingelman-Sundberg M, Oscarson M, Daly AK, Garte S, Nebert DW . Human cytochrome P-450 (CYP) genes: a web page for the nomenclature of alleles. Cancer Epidemiol Biomarkers Prev 2001; 10: 1307–1308.

    CAS  PubMed  Google Scholar 

  3. Sim SC, Ingelman-Sundberg M . The human cytochrome P450 (CYP) allele nomenclature website: a peer-reviewed database of CYP variants and their associated effects. Hum Genomics 2010; 4: 278–281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Goldstein JA . Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 2001; 52: 349–355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Xie HG, Kim RB, Wood AJ, Stein CM . Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol 2001; 41: 815–850.

    Article  CAS  PubMed  Google Scholar 

  6. Goldstein JA, Ishizaki T, Chiba K, de Morais SM, Bell D, Krahn PM et al. Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations. Pharmacogenetics 1997; 7: 59–64.

    Article  CAS  PubMed  Google Scholar 

  7. Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 2006; 79: 103–113.

    Article  CAS  PubMed  Google Scholar 

  8. Rudberg I, Mohebi B, Hermann M, Refsum H, Molden E . Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients. Clin Pharmacol Ther 2008; 83: 322–327.

    Article  CAS  PubMed  Google Scholar 

  9. Inomata S, Nagashima A, Itagaki F, Homma M, Nishimura M, Osaka Y et al. CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia. Clin Pharmacol Ther 2005; 78: 647–655.

    Article  CAS  PubMed  Google Scholar 

  10. Furuta T, Sugimoto M, Shirai N, Ishizaki T . CYP2C19 pharmacogenomics associated with therapy of Helicobacter pylori infection and gastro-esophageal reflux diseases with a proton pump inhibitor. Pharmacogenomics 2007; 8: 1199–1210.

    Article  CAS  PubMed  Google Scholar 

  11. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354–362.

    Article  CAS  PubMed  Google Scholar 

  12. Desta Z, Zhao X, Shin JG, Flockhart DA . Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41: 913–958.

    Article  CAS  PubMed  Google Scholar 

  13. Giusti B, Gori AM, Marcucci R, Saracini C, Sestini I, Paniccia R et al. Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10+12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genomics 2007; 17: 1057–1064.

    Article  CAS  PubMed  Google Scholar 

  14. Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244–2247.

    Article  CAS  PubMed  Google Scholar 

  15. Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet 2009; 373: 309–317.

    Article  CAS  PubMed  Google Scholar 

  16. Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 2009; 302: 849–857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360: 363–375.

    Article  CAS  PubMed  Google Scholar 

  18. Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthelemy O et al. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol 2010; 56: 134–143.

    Article  CAS  PubMed  Google Scholar 

  19. Sofi F, Giusti B, Marcucci R, Gori AM, Abbate R, Gensini GF . Cytochrome P450 2C19(*)2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis. Pharmacogenomics J 2010. Epub ahead of print.

  20. Paré G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med 2010; 363: 1704–1714.

    Article  PubMed  Google Scholar 

  21. FDA Drug Safety Communication: reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm. Accessed 13 December 2010.

  22. Ellis KJ, Stouffer GA, McLeod HL, Lee CR . Clopidogrel pharmacogenomics and risk of inadequate platelet inhibition: US FDA recommendations. Pharmacogenomics 2009; 10: 1799–1817.

    Article  CAS  PubMed  Google Scholar 

  23. Holmes Jr DR, Dehmer GJ, Kaul S, Leifer D, O’Gara PT, Stein CM . ACCF/AHA Clopidogrel clinical alert: approaches to the FDA ‘boxed warning’: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the American Heart Association. Circulation 2010; 122: 537–557.

    Article  PubMed  Google Scholar 

  24. Hulot JS, Wuerzner G, Bachelot-Loza C, Azizi M, Blanchard A, Peyrard S et al. Effect of an increased clopidogrel maintenance dose or lansoprazole co-administration on the antiplatelet response to clopidogrel in CYP2C19-genotyped healthy subjects. J Thromb Haemost 2010; 8: 610–613.

    Article  CAS  PubMed  Google Scholar 

  25. Roden DM, Shuldiner AR . Responding to the clopidogrel warning by the US food and drug administration: real life is complicated. Circulation 2010; 122: 445–448.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Seip RL, Duconge J, Ruano G . Implementing genotype-guided antithrombotic therapy. Future Cardiol 2010; 6: 409–424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Frere C, Cuisset T, Gaborit B, Alessi MC, Hulot JS . 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: 1409–1411.

    Article  CAS  PubMed  Google Scholar 

  28. Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 2010; 121: 512–518.

    Article  CAS  PubMed  Google Scholar 

  29. Sibbing D, Gebhard D, Koch W, Braun S, Stegherr J, Morath T et al. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J Thromb Haemost 2010; 8: 1685–1693.

    Article  CAS  PubMed  Google Scholar 

  30. Tiroch KA, Sibbing D, Koch W, Roosen-Runge T, Mehilli J, Schomig A et al. Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am Heart J 2010; 160: 506–512.

    Article  CAS  PubMed  Google Scholar 

  31. Li-Wan-Po A, Girard T, Farndon P, Cooley C, Lithgow J . Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17. Br J Clin Pharmacol 2010; 69: 222–230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ragia G, Arvanitidis KI, Tavridou A, Manolopoulos VG . Need for reassessment of reported CYP2C19 allele frequencies in various populations in view of CYP2C19*17 discovery: the case of Greece. Pharmacogenomics 2009; 10: 43–49.

    Article  CAS  PubMed  Google Scholar 

  33. Scott SA, Edelmann L, Kornreich R, Erazo M, Desnick RJ . CYP2C9, CYP2C19 and CYP2D6 allele frequencies in the Ashkenazi Jewish population. Pharmacogenomics 2007; 8: 721–730.

    Article  CAS  PubMed  Google Scholar 

  34. Ferguson RJ, De Morais SM, Benhamou S, Bouchardy C, Blaisdell J, Ibeanu G et al. A new genetic defect in human CYP2C19: mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin. J Pharmacol Exp Ther 1998; 284: 356–361.

    CAS  PubMed  Google Scholar 

  35. Garcia-Barcelo M, Chow LY, Kum Chiu HF, Wing YK, Shing Lee DT, Lam KL et al. Frequencies of defective CYP2C19 alleles in a Hong Kong Chinese population: detection of the rare allele CYP2C19*4. Clin Chem 1999; 45: 2273–2274.

    CAS  PubMed  Google Scholar 

  36. Taubert D, von Beckerath N, Grimberg G, Lazar A, Jung N, Goeser T et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 2006; 80: 486–501.

    Article  CAS  PubMed  Google Scholar 

  37. Spiewak M, Malek LA, Kostrzewa G, Kisiel B, Serafin A, Filipiak KJ et al. Influence of C3435T multidrug resistance gene-1 (MDR-1) polymorphism on platelet reactivity and prognosis in patients with acute coronary syndromes. Kardiol Pol 2009; 67: 827–834.

    PubMed  Google Scholar 

  38. Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 2010; 376: 1312–1319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Scott SA, Edelmann L, Kornreich R, Desnick RJ . Warfarin pharmacogenetics: CYP2C9 and VKORC1 genotypes predict different sensitivity and resistance frequencies in the Ashkenazi and Sephardi Jewish populations. Am J Hum Genet 2008; 82: 495–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Scott SA, Edelmann L, Liu L, Luo M, Desnick RJ, Kornreich R . Experience with carrier screening and prenatal diagnosis for 16 Ashkenazi Jewish genetic diseases. Hum Mutat 2010; 31: 1240–1250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J 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: 1320–1328.

    Article  CAS  PubMed  Google Scholar 

  42. Pedersen RS, Brasch-Andersen C, Sim SC, Bergmann TK, Halling J, Petersen MS et al. Linkage disequilibrium between the CYP2C19*17 allele and wildtype CYP2C8 and CYP2C9 alleles: identification of CYP2C haplotypes in healthy Nordic populations. Eur J Clin Pharmacol 2010; 66: 1199–1205.

    Article  PubMed  Google Scholar 

  43. Zhou Q, Yu XM, Lin HB, Wang L, Yun QZ, Hu SN et al. Genetic polymorphism, linkage disequilibrium, haplotype structure and novel allele analysis of CYP2C19 and CYP2D6 in Han Chinese. Pharmacogenomics J 2009; 9: 380–394.

    Article  CAS  PubMed  Google Scholar 

  44. Blaisdell J, Mohrenweiser H, Jackson J, Ferguson S, Coulter S, Chanas B et al. Identification and functional characterization of new potentially defective alleles of human CYP2C19. Pharmacogenetics 2002; 12: 703–711.

    Article  CAS  PubMed  Google Scholar 

  45. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000; 97: 3473–3478.

    Article  CAS  PubMed  Google Scholar 

  46. Nakamura T, Sakaeda T, Horinouchi M, Tamura T, Aoyama N, Shirakawa T et al. Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin Pharmacol Ther 2002; 71: 297–303.

    Article  CAS  PubMed  Google Scholar 

  47. Owen A, Goldring C, Morgan P, Chadwick D, Park BK, Pirmohamed M . Relationship between the C3435T and G2677T(A) polymorphisms in the ABCB1 gene and P-glycoprotein expression in human liver. Br J Clin Pharmacol 2005; 59: 365–370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cascorbi I, Gerloff T, Johne A, Meisel C, Hoffmeyer S, Schwab M et al. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 2001; 69: 169–174.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Joseph M Sweeny, Mount Sinai Medical Center, New York, and Dr Sarah Sim, Karolinska Institutet, Stockholm, Sweden, for critical reading of the manuscript. This research was supported in part by a research training grant (5 T32 GM082773) and a grant (UL1RR029887) for the Mount Sinai Institutes for Clinical and Translational Sciences from the National Center for Research Resources, National Institutes of Health. eSensor 2C19 Test reagents for this study were supplied by GenMark Diagnostics (Carlsbad, CA, USA).

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  1. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA

    S A Scott, S Martis, I Peter, Y Kasai, R Kornreich & R J Desnick

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Scott, S., Martis, S., Peter, I. et al. Identification of CYP2C19*4B: pharmacogenetic implications for drug metabolism including clopidogrel responsiveness. Pharmacogenomics J 12, 297–305 (2012). https://doi.org/10.1038/tpj.2011.5

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