Paraoxonase 1 Q192R Variant and Clopidogrel Efficacy
2012; Lippincott Williams & Wilkins; Volume: 5; Issue: 2 Linguagem: Catalão
10.1161/circgenetics.112.962910
ISSN1942-325X
AutoresJoshua P. Lewis, Alan R. Shuldiner,
Tópico(s)Coronary Interventions and Diagnostics
ResumoHomeCirculation: Cardiovascular GeneticsVol. 5, No. 2Paraoxonase 1 Q192R Variant and Clopidogrel Efficacy Free AccessEditorialPDF/EPUBAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBParaoxonase 1 Q192R Variant and Clopidogrel EfficacyFact or Fiction? Joshua P. Lewis, PhD and Alan R. Shuldiner, MD Joshua P. LewisJoshua P. Lewis From the Program in Personalized and Genomic Medicine (J.P.L., A.R.S.), Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine; and Geriatric Research and Education Clinical Center (A.R.S.), Veterans Administration Medical Center, Baltimore, MD. and Alan R. ShuldinerAlan R. Shuldiner From the Program in Personalized and Genomic Medicine (J.P.L., A.R.S.), Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine; and Geriatric Research and Education Clinical Center (A.R.S.), Veterans Administration Medical Center, Baltimore, MD. Originally published1 Apr 2012https://doi.org/10.1161/CIRCGENETICS.112.962910Circulation: Cardiovascular Genetics. 2012;5:153–155Clopidogrel, in combination with aspirin, is the standard of care for preventing ischemic cardiovascular events in patients with coronary artery disease, especially those who undergo percutaneous coronary intervention (PCI). Despite its widespread use, significant interindividual variability in clopidogrel response is consistently observed, and recent studies have suggested that as much as 70% of this variability can be attributed to genetic factors.1,2Article see p 250Clopidogrel is a thienopyridine prodrug that once activated, exerts its antiplatelet effect by irreversibly binding to the P2Y12 receptor on the surface of platelets inhibiting ADP-stimulated platelet aggregation. Clopidogrel activation requires a 2-step conversion by hepatic enzymes, most notably CYP2C19, whereas esterases (eg, carboxylesterase 1 and carboxylesterase 2) lead to the production of biologically inactive carboxylic acid derivatives.3 Common loss-of-function variants in CYP2C19 are associated with lower active metabolite levels, higher residual on-clopidogrel ADP-stimulated platelet aggregation, and poorer cardiovascular outcomes.3 However, this variant explains only ≈12% of the variation in platelet response to clopidogrel, leaving most of the heritable variation unknown.Recently, Bouman and colleagues4 observed through in vitro studies that paraoxonase 1 (PON1) was the major enzyme in converting 2-oxo-clopidogrel to the active thiol metabolite. Moreover, they reported that a common missense variant in PON1, Q192R, was a major determinant of clopidogrel efficacy, accounting for nearly 70% of the variability in ADP-stimulated platelet aggregation postclopidogrel treatment. 192Q PON1 had lower hydrolysis efficiency for 2-oxo-clopidogrel compared to 192R PON1 in microsomal preparations, and clopidogrel-treated PCI patients homozygous for the 192Q allele had a significantly higher rate of stent thrombosis compared with patients carrying at least 1 copy of the 192R allele. Curiously, no effect of the well-described CYP2C19*2 loss-of-function variant on clopidogrel response was observed in the same patient sample.In the past year, our group and several others have attempted to replicate these striking results, with little success.5–12 In this issue of Circulation: Cardiovascular Genetics, Paré and colleagues13 report efficacy and safety data regarding clopidogrel among PON1 Q192R genotypes in 2 of the largest prospective placebo-controlled trials studied to date: the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial14 and the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE A).15Consistent with the parent CURE trial report, in the subset of 5059 patients with acute coronary syndrome in this genetic substudy (2549 randomized to clopidogrel and 2510 randomized to placebo), clopidogrel-treated patients had lower cardiovascular event rates than placebo-treated patients (hazard ratio, 0.70; 95% CI, 0.59–0.84; P<0.001). There was no evidence of association between 192Q PON1 and the composite primary cardiovascular outcome in clopidogrel-treated patients (hazard ratio, 0.93 per Q allele; 95% CI, 0.76–1.13; P=0.46). Interestingly, placebo-treated patients had significantly increased incidence of the primary cardiovascular outcome (hazard ratio, 1.23 per Q allele; 95% CI, 1.03–1.47; P=0.03). These findings are consistent with a number of other (although not all) studies showing an association of PON1 variants with increased cardiovascular events, presumably as a result of their association with lower high-density lipoprotein cholesterol levels and increased underlying atherosclerotic burden.16 When comparing cardiovascular event rates in patients treated with clopidogrel to patients treated with placebo stratified by PON1 Q192R genotype to evaluate effect modification, clopidogrel-treated 192Q homozygotes had a significantly decreased risk of experiencing the primary outcome compared to placebo-treated 192Q homozygotes (8.5% versus 13.9%, respectively; P 10 years. PON1 is a 45-kDa high-density lipoprotein-associated arylesterase that is believed to have antiatherosclerotic properties through its ability to metabolize oxidized lipids of low-density lipoproteins. Furthermore, previous studies have shown that paraoxonase activity is significantly reduced in patients with ST-segment–elevation myocardial infarction, non–ST-segment–elevation myocardial infarction, or unstable angina compared with healthy controls.17 Consistent with these findings, the current investigation by Paré and colleagues13 shows a significant association between the decreased function PON1 192Q allele and increased cardiovascular events in placebo-treated patients. However, this association was not observed in patients treated with clopidogrel. This novel finding suggests that somehow clopidogrel can ameliorate the increased risk of cardiovascular events in 192Q allele carriers. As mentioned previously, the explanation for this observation may be that clopidogrel has its greatest effect in decreasing cardiovascular events in higher-risk patients. It is intriguing to speculate that this effect may be independent of clopidogrel inhibition of platelet function because we and others have shown that the 192Q allele is not associated with on-clopidogrel ADP-stimulated platelet aggregation.5–7,9,10Paré and colleagues13 conclude with a caution regarding interpretation of pharmacogenetic analyses in the absence of nontreated controls. Indeed, without such a control group, it is often difficult to determine whether observed associations are the result of drug–genotype interactions or represent an underlying effect that is independent of drug treatment. Although randomized placebo-controlled trials have and continue to be the gold standard in evidence-based medicine, these investigations are costly and inefficient in studies of variable drug response. Therefore, we believe that it is important to also consider complementary study designs and analytic approaches. For example, phenotypic characterization of surrogate end points before and after drug treatment (eg, ex vivo ADP-stimulated platelet aggregation in the case of clopidogrel pharmacogenetics) allows for patients to serve as their own controls.Given the current evidence base, should patients with an indication for antiplatelet therapy undergo PON1 genetic testing? Probably not. By contrast, there is a large body of converging evidence (pharmacokinetic, pharmacodynamic, clinical outcomes) supporting a role for CYP2C19 genetic testing to guide antiplatelet therapy in PCI patients. Despite this evidence, many cardiologists have resisted changing practice in lieu of a prospective randomized clinical trial of CYP2C19 genotype-directed antiplatelet therapy to demonstrate efficacy and cost-effectiveness. One such trial, the PAPI-2 (Pharmacogenomics of Anti-Platelet Intervention-2) study (http://clinicaltrials.gov/ct2/show/NCT01452152) is ongoing. Such studies as well as large meta analyses will offer the opportunity to further evaluate PON1 and other candidate gene variants. In addition, larger genome-wide studies will provide the opportunity to discover novel variants that influence clopidogrel response. Ultimately, with the discovery of additional genetic determinants of clopidogrel response, a panel of genetic tests may be used along with clinical data to guide more-effective personalized antiplatelet therapy. Currently, the evidence base does not support PON1 for inclusion in such a panel.DisclosuresDr Shuldiner receives grant support from the National Institutes of Health to study the pharmacogenomics of antiplatelet therapy. He is also a consultant for United States Diagnostic Standards, Inc. Dr Lewis reports no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Alan R. Shuldiner, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, 660 W Redwood St, Rm 494, Baltimore, MD 21201. E-mail [email protected]umaryland.eduReferences1. Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003; 107: 2908– 2913. LinkGoogle Scholar2. Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome p450 2c19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009; 302: 849– 857. CrossrefMedlineGoogle Scholar3. Yin T, Miyata T. Pharmacogenomics of clopidogrel: evidence and perspectives. Thromb Res. 2011; 128: 307– 316. CrossrefMedlineGoogle Scholar4. Bouman HJ, Schömig E, van Werkum JW, Velder J, Hackeng CM, Hirschhäuser C, C, Schmalz HG, ten Berg JM, Taubert D. Paraoxonase-1 is a major determinant of clopidogrel efficacy. Nat Med. 2011; 17: 110– 116. CrossrefMedlineGoogle Scholar5. Sibbing D, Koch W, Massberg S, Byrne RA, Mehilli J, Schulz S, Mayer K, Bernlochner I, Schömig A, Kastrati A. 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: 1605– 1613. CrossrefMedlineGoogle Scholar6. Lewis JP, Fisch AS, Ryan K, O'Connell JR, Gibson Q, Mitchell BD, Shen H, Tanner K, Horenstein RB, Pakzy R, Tantry US, Bliden KP, Gurbel PA, Shuldiner AR. Paraoxonase 1 (PON1) gene variants are not associated with clopidogrel response. Clin Pharmacol Ther. 2011; 90: 568– 574. CrossrefMedlineGoogle Scholar7. Trenk D, Hochholzer W, Fromm MF, Zolk O, Valina CM, Stratz C, Neumann FJ. Paraoxonase-1 Q192R polymorphism and antiplatelet effects of clopidogrel in patients undergoing elective coronary stent placement. Circ Cardiovasc Genet. 2011; 4: 429– 436. LinkGoogle Scholar8. Simon T, Steg PG, Becquemont L, Verstuyft C, Kotti S, Schiele F, Ferrari E, Drouet E, Grollier G, Danchin N. Effect of paraoxonase-1 polymorphism on clinical outcomes in patients treated with clopidogrel after an acute myocardial infarction. Clin Pharmacol Ther. 2011; 90: 561– 567. CrossrefMedlineGoogle Scholar9. Hulot JS, Collet JP, Cayla G, Silvain J, Allanic F, Bellemain-Appaix A, Scott SA, Montalescot G. CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients. Circ Cardiovasc Interv. 2011; 4: 422– 428. LinkGoogle Scholar10. Fontana P, James R, Barazer I, Berdagué P, Schved JF, Rebsamen M, Vuilleumier N, Reny JL. Relationship between paraoxonase-1 activity, its Q192R genetic variant and clopidogrel responsiveness in the ADRIE study. J Thromb Haemost. 2011; 9: 1664– 1666. CrossrefMedlineGoogle Scholar11. Bonello L, Camoin-Jau L, Mancini J, Bessereau J, Grosdidier C, Alessi MC, Ostorero M, Dignat-George F, Paganelli F. Factors associated with the failure of clopidogrel dose-adjustment according to platelet reactivity monitoring to optimize P2Y12-ADP receptor blockade. Thromb Res. In press. Google Scholar12. Delaney JT, Ramirez AH, Bowton E, Pulley JM, Basford MA, Schildcrout JS, Shi Y, Zink R, Oetjens M, Xu H, Cleator JH, Jahangir E, Ritchie MD, Masys DR, Roden DM, Crawford DC, Denny JC. Predicting clopidogrel response using DNA samples linked to an electronic health record. Clin Pharmacol Ther. 2012; 91: 257– 263. CrossrefMedlineGoogle Scholar13. Paré G, Ross S, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Fox KA, Eikelboom JW. Effect of PON1 Q192R genetic polymorphism on clopidogrel efficacy and cardiovascular events in the CURE and ACTIVE trials. Circ Cardiovasc Genet. 2012; 5: 250– 256. LinkGoogle Scholar14. Mehta SR, Yusuf S. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial programme; rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease. Eur Heart J. 2000; 21: 2033– 2041. CrossrefMedlineGoogle Scholar15. Active Steering Committee; ACTIVE Investigators; Connolly S, Yusuf S, Budaj A, Camm J, Chrolavicius S, Commerford PJ, Flather M, Fox KA, Hart R, Hohnloser S, Joyner C, Pfeffer M, Anand I, Arthur H, Avezum A, Bethala-Sithya M, Blumenthal M, Ceremuzynski L, De Caterina R, Diaz R, Flaker G, Frangin G, Franzosi MG, Gaudin C, Golitsyn S, Goldhaber S, Granger C, Halon D, Hermosillo A, Hunt D, Jansky P, Karatzas N, Keltai M, Lanas F, Lau CP, Le Heuzey JY, Lewis BS, Morais J, Morillo C, Oto A, Paolasso E, Peters RJ, Pfisterer M, Piegas L, Pipillis T, Proste C, Sitkei E, Swedberg K, Synhorst D, Talajic M, Trégou V, Valentin V, van Mieghem W, Weintraub W, Varigos J. Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events. Am Heart J. 2006; 151: 1187– 1193. CrossrefMedlineGoogle Scholar16. Bhattacharyya T, Nicholls SJ, Topol EJ, Zhang R, Yang X, Schmitt D, Fu X, Shao M, Brennan DM, Ellis SG, Brennan ML, Allayee H, Lusis AJ, Hazen SL. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA. 2008; 299: 1265– 1276. CrossrefMedlineGoogle Scholar17. Senturk T, Sarandol E, Gullulu S, Erdinc S, Ozdabakoglu O, Ozdemir B, Baran I, Arslan S, Aydinlar A. Serum arylesterase activity is negatively correlated with inflammatory markers in patients with acute coronary syndromes. Saudi Med J. 2009; 30: 334– 339. MedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Ruff C and Sabatine M (2018) Genomics-Guided Antithrombotic Therapy for Acute Coronary Syndromes Genomic and Precision Medicine, 10.1016/B978-0-12-801812-5.00003-2, (147-161), . Amin A, Sheau Chin L, Azri Mohamed Noor D, SK Abdul Kader M, Kah Hay Y and Ibrahim B (2017) The Personalization of Clopidogrel Antiplatelet Therapy: The Role of Integrative Pharmacogenetics and Pharmacometabolomics, Cardiology Research and Practice, 10.1155/2017/8062796, 2017, (1-17), . Ford N (2016) The Metabolism of Clopidogrel: CYP2C19 Is a Minor Pathway, The Journal of Clinical Pharmacology, 10.1002/jcph.769, 56:12, (1474-1483), Online publication date: 1-Dec-2016. Shaw S, Balasubramanian B, Bonacorsi S, Cortes J, Cao K, Chen B, Dai J, Decicco C, Goswami A, Guo Z, Hanson R, Humphreys W, Lam P, Li W, Mathur A, Maxwell B, Michaudel Q, Peng L, Pudzianowski A, Qiu F, Su S, Sun D, Tymiak A, Vokits B, Wang B, Wexler R, Wu D, Zhang Y, Zhao R and Baran P (2015) Synthesis of Biologically Active Piperidine Metabolites of Clopidogrel: Determination of Structure and Analyte Development, The Journal of Organic Chemistry, 10.1021/acs.joc.5b00632, 80:14, (7019-7032), Online publication date: 17-Jul-2015. Turner R and Pirmohamed M (2013) Cardiovascular Pharmacogenomics: Expectations and Practical Benefits, Clinical Pharmacology & Therapeutics, 10.1038/clpt.2013.234, 95:3, (281-293), Online publication date: 1-Mar-2014. Perry C and Shuldiner A (2013) Pharmacogenomics of anti-platelet therapy: how much evidence is enough for clinical implementation?, Journal of Human Genetics, 10.1038/jhg.2013.41, 58:6, (339-345), Online publication date: 1-Jun-2013. Fisch A, Perry C, Stephens S, Horenstein R and Shuldiner A (2013) Pharmacogenomics of Anti-platelet and Anti-coagulation Therapy, Current Cardiology Reports, 10.1007/s11886-013-0381-3, 15:7, Online publication date: 1-Jul-2013. Perła-Kaján J and Jakubowski H (2012) Paraoxonase 1 and homocysteine metabolism, Amino Acids, 10.1007/s00726-012-1321-z, 43:4, (1405-1417), Online publication date: 1-Oct-2012. Cardelli M, Marchegiani F, Corsonello A, Lattanzio F and Provinciali M (2013) A Review of Pharmacogenetics of Adverse Drug Reactions in Elderly People, Drug Safety, 10.1007/BF03319099, 35:S1, (3-20), Online publication date: 1-Jan-2012. April 2012Vol 5, Issue 2 Advertisement Article InformationMetrics © 2012 American Heart Association, Inc.https://doi.org/10.1161/CIRCGENETICS.112.962910 Originally publishedApril 1, 2012 KeywordsangioplastypharmacogeneticsaryldialkylphosphataseEditorialsclopidogrelPDF download Advertisement SubjectsGeneticsPharmacologyTreatment
Referência(s)