{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:07:22Z","timestamp":1788872842799,"version":"build-2803163510"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2019,9,3]],"date-time":"2019-09-03T00:00:00Z","timestamp":1567468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01 GM074518"],"award-info":[{"award-number":["U01 GM074518"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01 HL105198"],"award-info":[{"award-number":["U01 HL105198"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U19 HL065962"],"award-info":[{"award-number":["U19 HL065962"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL137922"],"award-info":[{"award-number":["R01 HL137922"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K23 GM102678"],"award-info":[{"award-number":["K23 GM102678"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims\u2003<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results\u2003<\/jats:title>\n                    <jats:p>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\u2009=\u2009129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P\u2009=\u20098.8 \u00d7 10\u221254; CES1 G143E, P\u2009=\u20091.3 \u00d7 10\u221216; CYP2C19*17, P\u2009=\u20099.5 \u00d7 10\u221210; CYP2B6 1294\u2009+\u200953\u2009C\u2009&amp;gt;\u2009T, P\u2009=\u20093.0 \u00d7 10\u22124; CYP2B6 516\u2009G\u2009&amp;gt;\u2009T, P\u2009=\u20091.0 \u00d7 10\u22123; CYP2C9*2, P\u2009=\u20091.2 \u00d7 10\u22123; and CYP2C9*3, P\u2009=\u20091.5 \u00d7 10\u22123). 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 (\u03b2\u2009=\u20090.17, SE 0.06, P\u2009=\u20090.01) and cardiovascular-related death (\u03b2\u2009=\u20090.43, SE 0.16, P\u2009=\u20090.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR)\u2009=\u20091.78, 95% confidence interval (CI) 1.14\u20132.76, P\u2009=\u20090.01] and cardiovascular death (OR\u2009=\u20094.39, 95% CI 1.35\u201314.27, P\u2009=\u20090.01) compared to patients who carried six or fewer of these alleles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion\u2003<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ehjcvp\/pvz045","type":"journal-article","created":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T01:01:53Z","timestamp":1567126913000},"page":"203-210","source":"Crossref","is-referenced-by-count":96,"title":["Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients"],"prefix":"10.1093","volume":"6","author":[{"given":"Joshua P","family":"Lewis","sequence":"first","affiliation":[{"name":"Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, 670 W. Baltimore St., Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7262-0880","authenticated-orcid":false,"given":"Joshua D","family":"Backman","sequence":"first","affiliation":[{"name":"Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, 670 W. Baltimore St., Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7528-7363","authenticated-orcid":false,"given":"Jean-Luc","family":"Reny","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, B\u00e9ziers Hospital, 2 Rue Valentin Hau, BP 740, B\u00e9ziers 34525, France"},{"name":"Department of Medicine, Geneva Platelet Group, University of Geneva School of Medicine, University Hospitals of Geneva, 24 rue du G\u00e9n\u00e9ral-Dufour, Gen\u00e8ve 4 CH-1211, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7900-9926","authenticated-orcid":false,"given":"Thomas O","family":"Bergmeijer","sequence":"first","affiliation":[{"name":"Department of Cardiology, Antonius Center for Platelet Function Research, St Antonius Hospital, P O Box 2500, Nieuwegein 3432 EM, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4920-4744","authenticated-orcid":false,"given":"Braxton D","family":"Mitchell","sequence":"first","affiliation":[{"name":"Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, 670 W. Baltimore St., Baltimore, MD 21201, USA"},{"name":"Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, 10 N. Greene St., Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1208-1720","authenticated-orcid":false,"given":"Marylyn D","family":"Ritchie","sequence":"first","affiliation":[{"name":"Center for Translational Bioinformatics, Institute for Biomedical Informatics, University of Pennsylvania, A301 Richards Building, 3700 Hamilton Walk, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"D\u00e9ry","sequence":"first","affiliation":[{"name":"Quebec Heart and Lung Institute, University Laval, 2725 chemin Sainte-Foy, Quebec City G1V 4G5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth E","family":"Pakyz","sequence":"first","affiliation":[{"name":"Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, 670 W. Baltimore St., Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1739-8233","authenticated-orcid":false,"given":"Li","family":"Gong","sequence":"first","affiliation":[{"name":"Department of Biomedical Data Science, Stanford University, 443 Via Ortega, Room 213, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Ryan","sequence":"first","affiliation":[{"name":"Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, 670 W. Baltimore St., Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Young","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Bokji-ro 75, Busangjin-gu, Busan 614-735, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Aradi","sequence":"first","affiliation":[{"name":"Department of Cardiology, Heart Center Balatonf\u00fcred, 2 Gyogy Ter, Balatonfured 8230, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Israel","family":"Fernandez-Cadenas","sequence":"first","affiliation":[{"name":"Stroke Pharmacogenomics and Genetic Group, Fundaci\u00f3 Docencia i Recerca Mutuaterrassa, 508221 Terrassa, Barcelona 8041, Spain"},{"name":"Department of Neurology, Vall d'Hebron Institute of Research, Passeig Vall d'Hebron, Barcelona 8035, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming Ta Michael","family":"Lee","sequence":"first","affiliation":[{"name":"Genomic Medicine Institute, Geisinger Health System, 100 N. Academy Ave., Danville, PA 17822, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8810-3893","authenticated-orcid":false,"given":"Ryan M","family":"Whaley","sequence":"first","affiliation":[{"name":"Department of Biomedical Data Science, Stanford University, 443 Via Ortega, Room 213, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan","family":"Montaner","sequence":"first","affiliation":[{"name":"Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Passeig Vall d'Hebron 119-129, Barcelona 8035, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gian Franco","family":"Gensini","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla, Florence 50055, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John H","family":"Cleator","sequence":"first","affiliation":[{"name":"Division of Cardiology, Vanderbilt University Medical Center, 2215B Garland Avenue, Nashville, TN 37232, USA"},{"name":"Department of Pharmacology, Vanderbilt University Medical Center, 2215B Garland Avenue, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3456-8705","authenticated-orcid":false,"given":"Kiyuk","family":"Chang","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lene","family":"Holmvang","sequence":"first","affiliation":[{"name":"Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Inge Lehmannsvej 7 - 2142, Copenhagen 2100, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willibald","family":"Hochholzer","sequence":"first","affiliation":[{"name":"Department of Cardiology and Angiology II, University Heart Center Freiburg, Suedring 15, Bad Krozingen 79189, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6302-0389","authenticated-orcid":false,"given":"Dan M","family":"Roden","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Vanderbilt University Medical Center, 2215B Garland Avenue, Nashville, TN 37232, USA"},{"name":"Department of Medicine, Vanderbilt University Medical Center, 2215B Garland Avenue, Nashville, TN 37232, USA"},{"name":"Department of Biomedical Informatics, Vanderbilt University Medical Center, 2215B Garland Avenue, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Winter","sequence":"first","affiliation":[{"name":"Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, Stuttgart, 70376 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3859-2905","authenticated-orcid":false,"given":"Russ B","family":"Altman","sequence":"first","affiliation":[{"name":"Department of Bioengineering, Genetics, and Medicine, Stanford University, 443 Via Ortega Drive, Shriram Room 209, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Alexopoulos","sequence":"first","affiliation":[{"name":"Department of Cardiology, Patras University Hospital, Rio, Patras 26500, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ho-Sook","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Gaegum2-dong 622-165, Busanjin-Gu, Busan 614-735, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meinrad","family":"Gawaz","sequence":"first","affiliation":[{"name":"Department of Cardiology and Angiology, University of T\u00fcbingen, Otfired-M\u00fcller-Stra\u00dfe 10, T\u00fcbingen 72076, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin P","family":"Bliden","sequence":"first","affiliation":[{"name":"Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, 3300 Gallows Rd, Falls Church, VA 22042, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Valgimigli","sequence":"first","affiliation":[{"name":"Department of Cardiology, Bern University Hospital, Freiburgstrasse 8, Bern 3010, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Marcucci","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla, Florence 50055, Italy"},{"name":"Atherothrombotic Diseases Center, Careggi University Hospital, Largo G. Alessandro Brambilla, Florence 50134, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5150-188X","authenticated-orcid":false,"given":"Gianluca","family":"Campo","sequence":"first","affiliation":[{"name":"Department of Cardiology, University Hospital of Ferrara, Via Aldo Moro 8, Cona (FE), Ferrara 44123, Italy"},{"name":"GVM Care & Research, Maria Cecilia Hospital, Via Madonna di Genova, 1, Cotignola 48033, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"Schaeffeler","sequence":"first","affiliation":[{"name":"Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, Stuttgart, 70376 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia P","family":"Dridi","sequence":"first","affiliation":[{"name":"Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Inge Lehmannsvej 7 - 2142, Copenhagen 2100, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Shien","family":"Wen","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Gook","family":"Shin","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Gaegum2-dong 622-165, Busanjin-Gu, Busan 614-735, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1546-0774","authenticated-orcid":false,"given":"Pierre","family":"Fontana","sequence":"first","affiliation":[{"name":"Department of Medicine, Geneva Platelet Group, University of Geneva School of Medicine, University Hospitals of Geneva, 24 rue du G\u00e9n\u00e9ral-Dufour, Gen\u00e8ve 4 CH-1211, Switzerland"},{"name":"Division of Angiology and Haemostasis, University Hospitals of Geneva, 24 Rue Gabrielle-Perret-Gentil, Geneva 1205, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betti","family":"Giusti","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla, Florence 50055, Italy"},{"name":"Atherothrombotic Diseases Center, Careggi University Hospital, Largo G. Alessandro Brambilla, Florence 50134, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Geisler","sequence":"first","affiliation":[{"name":"Department of Cardiology and Angiology, University of T\u00fcbingen, Otfired-M\u00fcller-Stra\u00dfe 10, T\u00fcbingen 72076, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiaki","family":"Kubo","sequence":"first","affiliation":[{"name":"Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, 1-7-22, Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0505-7121","authenticated-orcid":false,"given":"Dietmar","family":"Trenk","sequence":"first","affiliation":[{"name":"Department of Cardiology and Angiology II, Clinical Pharmacology, University Heart Centre Freiburg, Suedring 15, Bad Krozingen D-79189, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6041-1635","authenticated-orcid":false,"given":"Jolanta M","family":"Siller-Matula","sequence":"first","affiliation":[{"name":"Department of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jurri\u00ebn M","family":"ten Berg","sequence":"first","affiliation":[{"name":"Department of Cardiology, Antonius Center for Platelet Function Research, St Antonius Hospital, P O Box 2500, Nieuwegein 3432 EM, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A","family":"Gurbel","sequence":"first","affiliation":[{"name":"Department of Cardiology and Angiology, University of T\u00fcbingen, Otfired-M\u00fcller-Stra\u00dfe 10, T\u00fcbingen 72076, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Schwab","sequence":"first","affiliation":[{"name":"Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, Stuttgart, 70376 Germany"},{"name":"Department of Clinical Pharmacology, University of Tuebingen, Otfried-Mueller-Strasse 10, Tuebingen 72076, Germany"},{"name":"Department of Pharmacy and Biochemistry, University of Tuebingen, Otfried-Mueller-Strasse 10, Tuebingen 72076, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teri E","family":"Klein","sequence":"first","affiliation":[{"name":"Department of Biomedical Data Science, Stanford University, 443 Via Ortega, Room 213, Stanford, CA 94305, USA"},{"name":"Department of Bioengineering, Genetics, and Medicine, Stanford University, 443 Via Ortega Drive, Shriram Room 209, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan R","family":"Shuldiner","sequence":"first","affiliation":[{"name":"Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, 670 W. 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