Joshua P Lewis1, Joshua D Backman1, Jean-Luc Reny2,3, Thomas O Bergmeijer4, Braxton D Mitchell1,5, Marylyn D Ritchie6, Jean-Pierre Déry7, Ruth E Pakyz1, Li Gong8, Kathleen Ryan1, Eun-Young Kim9, Daniel Aradi10, Israel Fernandez-Cadenas11,12, Ming Ta Michael Lee13, Ryan M Whaley8, Joan Montaner14, Gian Franco Gensini15, John H Cleator16,17, Kiyuk Chang18, Lene Holmvang19, Willibald Hochholzer20, Dan M Roden17,21,22, Stefan Winter23, Russ B Altman24, Dimitrios Alexopoulos25, Ho-Sook Kim26, Meinrad Gawaz27, Kevin P Bliden28, Marco Valgimigli29, Rossella Marcucci15,30, Gianluca Campo31,32, Elke Schaeffeler23, Nadia P Dridi19, Ming-Shien Wen33, Jae Gook Shin26, Pierre Fontana3,34, Betti Giusti15,30, Tobias Geisler27, Michiaki Kubo35, Dietmar Trenk36, Jolanta M Siller-Matula37, Jurriën M Ten Berg4, Paul A Gurbel27, Matthias Schwab23,38,39, Teri E Klein8,24, Alan R Shuldiner1. 1. Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, 670 W. Baltimore St., Baltimore, MD 21201, USA. 2. Department of Internal Medicine, Béziers Hospital, 2 Rue Valentin Hau, BP 740, Béziers 34525, France. 3. Department of Medicine, Geneva Platelet Group, University of Geneva School of Medicine, University Hospitals of Geneva, 24 rue du Général-Dufour, Genève 4 CH-1211, Switzerland. 4. Department of Cardiology, Antonius Center for Platelet Function Research, St Antonius Hospital, P O Box 2500, Nieuwegein 3432 EM, The Netherlands. 5. Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, 10 N. Greene St., Baltimore, MD 21201, USA. 6. Center for Translational Bioinformatics, Institute for Biomedical Informatics, University of Pennsylvania, A301 Richards Building, 3700 Hamilton Walk, Philadelphia, PA 19104, USA. 7. Quebec Heart and Lung Institute, University Laval, 2725 chemin Sainte-Foy, Quebec City G1V 4G5, Canada. 8. Department of Biomedical Data Science, Stanford University, 443 Via Ortega, Room 213, Stanford, CA 94305, USA. 9. Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Bokji-ro 75, Busangjin-gu, Busan 614-735, South Korea. 10. Department of Cardiology, Heart Center Balatonfüred, 2 Gyogy Ter, Balatonfured 8230, Hungary. 11. Stroke Pharmacogenomics and Genetic Group, Fundació Docencia i Recerca Mutuaterrassa, 508221 Terrassa, Barcelona 8041, Spain. 12. Department of Neurology, Vall d'Hebron Institute of Research, Passeig Vall d'Hebron, Barcelona 8035, Spain. 13. Genomic Medicine Institute, Geisinger Health System, 100 N. Academy Ave., Danville, PA 17822, USA. 14. Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Passeig Vall d'Hebron 119-129, Barcelona 8035, Spain. 15. Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla, Florence 50055, Italy. 16. Division of Cardiology, Vanderbilt University Medical Center, 2215B Garland Avenue, Nashville, TN 37232, USA. 17. Department of Pharmacology, Vanderbilt University Medical Center, 2215B Garland Avenue, Nashville, TN 37232, USA. 18. Department of Internal Medicine, Cardiology Division, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-Gu, Seoul 6591, South Korea. 19. Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Inge Lehmannsvej 7 - 2142, Copenhagen 2100, Denmark. 20. Department of Cardiology and Angiology II, University Heart Center Freiburg, Suedring 15, Bad Krozingen 79189, Germany. 21. Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Avenue, Nashville, TN 37232, USA. 22. Department of Biomedical Informatics, Vanderbilt University Medical Center, 2215B Garland Avenue, Nashville, TN 37232, USA. 23. Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, Stuttgart, 70376 Germany. 24. Department of Bioengineering, Genetics, and Medicine, Stanford University, 443 Via Ortega Drive, Shriram Room 209, Stanford, CA 94305, USA. 25. Department of Cardiology, Patras University Hospital, Rio, Patras 26500, Greece. 26. Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Gaegum2-dong 622-165, Busanjin-Gu, Busan 614-735, South Korea. 27. Department of Cardiology and Angiology, University of Tübingen, Otfired-Müller-Straße 10, Tübingen 72076, Germany. 28. Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, 3300 Gallows Rd, Falls Church, VA 22042, USA. 29. Department of Cardiology, Bern University Hospital, Freiburgstrasse 8, Bern 3010, Switzerland. 30. Atherothrombotic Diseases Center, Careggi University Hospital, Largo G. Alessandro Brambilla, Florence 50134, Italy. 31. Department of Cardiology, University Hospital of Ferrara, Via Aldo Moro 8, Cona (FE), Ferrara 44123, Italy. 32. GVM Care & Research, Maria Cecilia Hospital, Via Madonna di Genova, 1, Cotignola 48033, Italy. 33. Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou and School of Medicine, Chang Gung University, No. 5, Fuxing St, Guishan Dist., Taoyuan City 333, Taiwan. 34. Division of Angiology and Haemostasis, University Hospitals of Geneva, 24 Rue Gabrielle-Perret-Gentil, Geneva 1205, Switzerland. 35. Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, 1-7-22, Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan. 36. Department of Cardiology and Angiology II, Clinical Pharmacology, University Heart Centre Freiburg, Suedring 15, Bad Krozingen D-79189, Germany. 37. Department of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria. 38. Department of Clinical Pharmacology, University of Tuebingen, Otfried-Mueller-Strasse 10, Tuebingen 72076, Germany. 39. Department of Pharmacy and Biochemistry, University of Tuebingen, Otfried-Mueller-Strasse 10, Tuebingen 72076, Germany.
Abstract
AIMS: Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial. METHODS AND RESULTS: We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10-54; CES1 G143E, P = 1.3 × 10-16; CYP2C19*17, P = 9.5 × 10-10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10-4; CYP2B6 516 G > T, P = 1.0 × 10-3; CYP2C9*2, P = 1.2 × 10-3; and CYP2C9*3, P = 1.5 × 10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14-2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35-14.27, P = 0.01) compared to patients who carried six or fewer of these alleles. CONCLUSION: Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial. METHODS AND RESULTS: We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery diseasepatients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10-54; CES1G143E, P = 1.3 × 10-16; CYP2C19*17, P = 9.5 × 10-10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10-4; CYP2B6 516 G > T, P = 1.0 × 10-3; CYP2C9*2, P = 1.2 × 10-3; and CYP2C9*3, P = 1.5 × 10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14-2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35-14.27, P = 0.01) compared to patients who carried six or fewer of these alleles. CONCLUSION: Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Donald E Cutlip; Stephan Windecker; Roxana Mehran; Ashley Boam; David J Cohen; Gerrit-Anne van Es; P Gabriel Steg; Marie-angèle Morel; Laura Mauri; Pascal Vranckx; Eugene McFadden; Alexandra Lansky; Martial Hamon; Mitchell W Krucoff; Patrick W Serruys Journal: Circulation Date: 2007-05-01 Impact factor: 29.690
Authors: Sarah C Sim; Carl Risinger; Marja-Liisa Dahl; Eleni Aklillu; Magnus Christensen; Leif Bertilsson; Magnus Ingelman-Sundberg Journal: Clin Pharmacol Ther Date: 2006-01 Impact factor: 6.875
Authors: Ezra A Amsterdam; Nanette K Wenger; Ralph G Brindis; Donald E Casey; Theodore G Ganiats; David R Holmes; Allan S Jaffe; Hani Jneid; Rosemary F Kelly; Michael C Kontos; Glenn N Levine; Philip R Liebson; Debabrata Mukherjee; Eric D Peterson; Marc S Sabatine; Richard W Smalling; Susan J Zieman Journal: J Am Coll Cardiol Date: 2014-09-23 Impact factor: 24.094
Authors: Nisha Nanda; Ming Bao; Hanna Lin; Karl Clauser; Laszlo Komuves; Thomas Quertermous; Pamela B Conley; David R Phillips; Matthew J Hart Journal: J Biol Chem Date: 2005-04-25 Impact factor: 5.157
Authors: Lars Wallentin; Stefan James; Robert F Storey; Martin Armstrong; Bryan J Barratt; Jay Horrow; Steen Husted; Hugo Katus; P Gabriel Steg; Svati H Shah; Richard C Becker Journal: Lancet Date: 2010-10-16 Impact factor: 79.321
Authors: Tabassome Simon; Céline Verstuyft; Murielle Mary-Krause; Lina Quteineh; Elodie Drouet; Nicolas Méneveau; P Gabriel Steg; Jean Ferrières; Nicolas Danchin; Laurent Becquemont Journal: N Engl J Med Date: 2008-12-22 Impact factor: 91.245
Authors: S A Scott; K Sangkuhl; C M Stein; J-S Hulot; J L Mega; D M Roden; T E Klein; M S Sabatine; J A Johnson; A R Shuldiner Journal: Clin Pharmacol Ther Date: 2013-05-22 Impact factor: 6.875
Authors: Xi-Ling Jiang; Snehal Samant; Joshua P Lewis; Richard B Horenstein; Alan R Shuldiner; Laura M Yerges-Armstrong; Lambertus A Peletier; Lawrence J Lesko; Stephan Schmidt Journal: Eur J Pharm Sci Date: 2015-10-30 Impact factor: 4.384
Authors: Larisa H Cavallari; Craig R Lee; Amber L Beitelshees; Rhonda M Cooper-DeHoff; Julio D Duarte; Deepak Voora; Stephen E Kimmel; Caitrin W McDonough; Yan Gong; Chintan V Dave; Victoria M Pratt; Tameka D Alestock; R David Anderson; Jorge Alsip; Amer K Ardati; Brigitta C Brott; Lawrence Brown; Supatat Chumnumwat; Michael J Clare-Salzler; James C Coons; Joshua C Denny; Chrisly Dillon; Amanda R Elsey; Issam S Hamadeh; Shuko Harada; William B Hillegass; Lindsay Hines; Richard B Horenstein; Lucius A Howell; Linda J B Jeng; Mark D Kelemen; Yee Ming Lee; Oyunbileg Magvanjav; May Montasser; David R Nelson; Edith A Nutescu; Devon C Nwaba; Ruth E Pakyz; Kathleen Palmer; Josh F Peterson; Toni I Pollin; Alison H Quinn; Shawn W Robinson; Jamie Schub; Todd C Skaar; D Max Smith; Vindhya B Sriramoju; Petr Starostik; Tomasz P Stys; James M Stevenson; Nicholas Varunok; Mark R Vesely; Dyson T Wake; Karen E Weck; Kristin W Weitzel; Russell A Wilke; James Willig; Richard Y Zhao; Rolf P Kreutz; George A Stouffer; Philip E Empey; Nita A Limdi; Alan R Shuldiner; Almut G Winterstein; Julie A Johnson Journal: JACC Cardiovasc Interv Date: 2017-11-01 Impact factor: 11.195
Authors: Joshua P Lewis; Moeen Riaz; Sophia Xie; Galina Polekhina; Rory Wolfe; Mark Nelson; Andrew M Tonkin; Christopher M Reid; Anne M Murray; John J McNeil; Alan R Shuldiner; Paul Lacaze Journal: Clin Pharmacol Ther Date: 2020-07-20 Impact factor: 6.875
Authors: David E Lanfear; Jasmine A Luzum; Ruicong She; Hongsheng Gui; Mark P Donahue; Christopher M O'Connor; Kirkwood F Adams; Sandra Sanders-van Wijk; Nicole Zeld; Micha T Maeder; Hani N Sabbah; William E Kraus; Hans-Peter Brunner-LaRocca; Jia Li; L Keoki Williams Journal: Circ Heart Fail Date: 2020-10-04 Impact factor: 8.790
Authors: Shefali Setia Verma; Thomas O Bergmeijer; Li Gong; Jean-Luc Reny; Joshua P Lewis; Braxton D Mitchell; Dimitrios Alexopoulos; Daniel Aradi; Russ B Altman; Kevin Bliden; Yuki Bradford; Gianluca Campo; Kiyuk Chang; John H Cleator; Jean-Pierre Déry; Nadia P Dridi; Israel Fernandez-Cadenas; Pierre Fontana; Meinrad Gawaz; Tobias Geisler; Gian Franco Gensini; Betti Giusti; Paul A Gurbel; Willibald Hochholzer; Lene Holmvang; Eun-Young Kim; Ho-Sook Kim; Rossella Marcucci; Joan Montaner; Joshua D Backman; Ruth E Pakyz; Dan M Roden; Elke Schaeffeler; Matthias Schwab; Jae Gook Shin; Jolanta M Siller-Matula; Jurriën M Ten Berg; Dietmar Trenk; Marco Valgimigli; John Wallace; Ming-Shien Wen; Michiaki Kubo; Ming Ta Michael Lee; Ryan Whaley; Stefan Winter; Teri E Klein; Alan R Shuldiner; Marylyn D Ritchie Journal: Clin Pharmacol Ther Date: 2020-07-09 Impact factor: 6.875
Authors: Craig R Lee; Cameron D Thomas; Amber L Beitelshees; Sony Tuteja; Philip E Empey; James C Lee; Nita A Limdi; Julio D Duarte; Todd C Skaar; Yiqing Chen; Kelsey J Cook; James C Coons; Chrisly Dillon; Francesco Franchi; Jay Giri; Yan Gong; Rolf P Kreutz; Caitrin W McDonough; James M Stevenson; Karen E Weck; Dominick J Angiolillo; Julie A Johnson; George A Stouffer; Larisa H Cavallari Journal: Clin Pharmacol Ther Date: 2020-10-02 Impact factor: 6.875