Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium.
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Verma SS
Department of Genetics and Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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Bergmeijer TO
Department of Cardiology, St. Antonius Center for Platelet Function Research, Nieuwegein, The Netherlands.
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Gong L
Department of Biomedical Data Science, Stanford University, Stanford, California, USA.
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Reny JL
Internal Medicine, Béziers Hospital, Béziers, France.
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Lewis JP
Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, Maryland, USA.
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Mitchell BD
Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, Maryland, USA.
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Alexopoulos D
National and Kapodistrian University of Athens Medical School, Attikon University Hospital, Athens, Greece.
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Aradi D
Department of Cardiology, Heart Center Balatonfüred, Balatonfüred, Hungary.
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Altman RB
Department of Bioengineering, Genetics and Medicine, Stanford University, Stanford, California, USA.
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Bliden K
Sinai Center for Thrombosis Research and Drug Development, Baltimore, Maryland, USA.
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Bradford Y
Department of Genetics and Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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Campo G
Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara and Maria Cecilia Hospital, GVM Care and Research, Cotignola, Italy.
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Chang K
Department of Internal Medicine, Cardiology Division, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.
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Cleator JH
Division of Cardiology and Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
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Déry JP
Quebec Heart and Lung Institute, University Laval, Quebec City, QC, Canada.
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Dridi NP
Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
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Fernandez-Cadenas I
Neurology, Stroke Pharmacogenomics and Genetics Group, Sant Pau Institute of Research, Barcelona, Spain.
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Fontana P
Department of Biomedical Data Science, Stanford University, Stanford, California, USA.
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Gawaz M
Department of Cardiology and Angiology, University of Tübingen, Tübingen, Germany.
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Geisler T
Department of Cardiology and Angiology, Medizinische Klinik III, University Hospital Tübingen, Tübingen, Germany.
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Gensini GF
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
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Giusti B
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
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Gurbel PA
Sinai Center for Thrombosis Research and Drug Development, Baltimore, Maryland, USA.
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Hochholzer W
Department of Cardiology and Angiology II, University Heart Center Freiburg Bad Krozingen, Bad Krozingen, Germany.
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Holmvang L
Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
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Kim EY
Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, South Korea.
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Kim HS
Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, South Korea.
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Marcucci R
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
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Montaner J
Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Barcelona, Spain.
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Backman JD
Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, Maryland, USA.
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Pakyz RE
Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, Maryland, USA.
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Roden DM
Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
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Schaeffeler E
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Tübingen, Germany.
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Schwab M
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Tübingen, Germany.
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Shin JG
Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, South Korea.
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Siller-Matula JM
Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.
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Ten Berg JM
Department of Cardiology, St. Antonius Center for Platelet Function Research, Nieuwegein, The Netherlands.
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Trenk D
Department of Cardiology and Angiology II, University Heart Center Freiburg Bad Krozingen, Bad Krozingen, Germany.
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Valgimigli M
Department of Cardiology, Swiss Cardiovascular Center Bern, Bern University Hospital, Bern, Switzerland.
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Wallace J
Department of Biochemistry and Molecular Biology, Penn State University, University Park, Pennsylvania, USA.
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Wen MS
Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou and School of Medicine, Chang Gung University, Taoyuan City, Taiwan.
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Kubo M
Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
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Lee MTM
Genomic Medicine Institute, Geisinger, Danville, Pennsylvania, USA.
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Whaley R
Department of Biomedical Data Science, Stanford University, Stanford, California, USA.
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Winter S
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Tübingen, Germany.
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Klein TE
Department of Biomedical Data Science, Stanford University, Stanford, California, USA.
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Shuldiner AR
Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, Maryland, USA.
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Ritchie MD
Department of Genetics and Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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Published in:
- Clinical pharmacology and therapeutics. - 2020
English
Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate-induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e-33). After correction for CYP2C19*2 no other single-nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e-09, 4.53e-08, and 2.60e-10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.
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hybrid
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https://folia.unifr.ch/global/documents/217659
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