Journal article

Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium.

  • Verma SS Department of Genetics and Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Bergmeijer TO Department of Cardiology, St. Antonius Center for Platelet Function Research, Nieuwegein, The Netherlands.
  • Gong L Department of Biomedical Data Science, Stanford University, Stanford, California, USA.
  • Reny JL Internal Medicine, Béziers Hospital, Béziers, France.
  • Lewis JP Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, Maryland, USA.
  • Mitchell BD Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, Maryland, USA.
  • Alexopoulos D National and Kapodistrian University of Athens Medical School, Attikon University Hospital, Athens, Greece.
  • Aradi D Department of Cardiology, Heart Center Balatonfüred, Balatonfüred, Hungary.
  • Altman RB Department of Bioengineering, Genetics and Medicine, Stanford University, Stanford, California, USA.
  • Bliden K Sinai Center for Thrombosis Research and Drug Development, Baltimore, Maryland, USA.
  • Bradford Y Department of Genetics and Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • Campo G Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara and Maria Cecilia Hospital, GVM Care and Research, Cotignola, Italy.
  • Chang K Department of Internal Medicine, Cardiology Division, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.
  • Cleator JH Division of Cardiology and Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Déry JP Quebec Heart and Lung Institute, University Laval, Quebec City, QC, Canada.
  • Dridi NP Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Fernandez-Cadenas I Neurology, Stroke Pharmacogenomics and Genetics Group, Sant Pau Institute of Research, Barcelona, Spain.
  • Fontana P Department of Biomedical Data Science, Stanford University, Stanford, California, USA.
  • Gawaz M Department of Cardiology and Angiology, University of Tübingen, Tübingen, Germany.
  • Geisler T Department of Cardiology and Angiology, Medizinische Klinik III, University Hospital Tübingen, Tübingen, Germany.
  • Gensini GF Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
  • Giusti B Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
  • Gurbel PA Sinai Center for Thrombosis Research and Drug Development, Baltimore, Maryland, USA.
  • Hochholzer W Department of Cardiology and Angiology II, University Heart Center Freiburg Bad Krozingen, Bad Krozingen, Germany.
  • Holmvang L Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Kim EY Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, South Korea.
  • Kim HS Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, South Korea.
  • Marcucci R Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
  • Montaner J Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Barcelona, Spain.
  • Backman JD Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, Maryland, USA.
  • Pakyz RE Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, Maryland, USA.
  • Roden DM Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Schaeffeler E Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Tübingen, Germany.
  • Schwab M Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Tübingen, Germany.
  • Shin JG Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, South Korea.
  • Siller-Matula JM Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.
  • Ten Berg JM Department of Cardiology, St. Antonius Center for Platelet Function Research, Nieuwegein, The Netherlands.
  • Trenk D Department of Cardiology and Angiology II, University Heart Center Freiburg Bad Krozingen, Bad Krozingen, Germany.
  • Valgimigli M Department of Cardiology, Swiss Cardiovascular Center Bern, Bern University Hospital, Bern, Switzerland.
  • Wallace J Department of Biochemistry and Molecular Biology, Penn State University, University Park, Pennsylvania, USA.
  • Wen MS Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou and School of Medicine, Chang Gung University, Taoyuan City, Taiwan.
  • Kubo M Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
  • Lee MTM Genomic Medicine Institute, Geisinger, Danville, Pennsylvania, USA.
  • Whaley R Department of Biomedical Data Science, Stanford University, Stanford, California, USA.
  • Winter S Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Tübingen, Germany.
  • Klein TE Department of Biomedical Data Science, Stanford University, Stanford, California, USA.
  • Shuldiner AR Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, Maryland, USA.
  • Ritchie MD Department of Genetics and Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Show more…
  • 2020-05-31
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.
Language
  • English
Open access status
hybrid
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/217659
Statistics

Document views: 28 File downloads:
  • Full-text: 0