Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC)

Thomas O Bergmeijer; Jean-Luc Reny; Ruth E Pakyz; Li Gong; Joshua P Lewis; Eun-Young Kim; Daniel Aradi; Israel Fernandez-Cadenas; Richard B Horenstein; Ming Ta Michael Lee; Ryan M Whaley; Joan Montaner; Gian Franco Gensini; John H Cleator; Kiyuk Chang; Lene Holmvang; Willibald Hochholzer; Dan M Roden; Stefan Winter; Russ B Altman; Dimitrios Alexopoulos; Ho-Sook Kim; Jean-Pierre Déry; Meinrad Gawaz; Kevin Bliden; Marco Valgimigli; Rossella Marcucci; Gianluca Campo; Elke Schaeffeler; Nadia P Dridi; Ming-Shien Wen; Jae Gook Shin; Tabassome Simon; Pierre Fontana; Betti Giusti; Tobias Geisler; Michiaki Kubo; Dietmar Trenk; Jolanta M Siller-Matula; Jurriën M Ten Berg; Paul A Gurbel; Jean-Sebastien Hulot; Braxton D Mitchell; Matthias Schwab; Marylyn DeRiggi Ritchie; Teri E Klein; Alan R Shuldiner; ICPC Investigators

doi:10.1016/j.ahj.2017.12.010

Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC)

Am Heart J. 2018 Apr:198:152-159. doi: 10.1016/j.ahj.2017.12.010. Epub 2017 Dec 17.

Authors

Thomas O Bergmeijer¹, Jean-Luc Reny², Ruth E Pakyz³, Li Gong⁴, Joshua P Lewis³, Eun-Young Kim⁵, Daniel Aradi⁶, Israel Fernandez-Cadenas⁷, Richard B Horenstein³, Ming Ta Michael Lee⁸, Ryan M Whaley⁴, Joan Montaner⁹, Gian Franco Gensini¹⁰, John H Cleator¹¹, Kiyuk Chang¹², Lene Holmvang¹³, Willibald Hochholzer¹⁴, Dan M Roden¹⁵, Stefan Winter¹⁶, Russ B Altman¹⁷, Dimitrios Alexopoulos¹⁸, Ho-Sook Kim¹⁹, Jean-Pierre Déry²⁰, Meinrad Gawaz²¹, Kevin Bliden²², Marco Valgimigli²³, Rossella Marcucci²⁴, Gianluca Campo²⁵, Elke Schaeffeler¹⁶, Nadia P Dridi¹³, Ming-Shien Wen²⁶, Jae Gook Shin¹⁹, Tabassome Simon²⁷, Pierre Fontana²⁸, Betti Giusti²⁴, Tobias Geisler²¹, Michiaki Kubo²⁹, Dietmar Trenk²¹, Jolanta M Siller-Matula³⁰, Jurriën M Ten Berg¹, Paul A Gurbel²², Jean-Sebastien Hulot³¹, Braxton D Mitchell³², Matthias Schwab³³, Marylyn DeRiggi Ritchie³⁴, Teri E Klein³⁵, Alan R Shuldiner³⁶; ICPC Investigators

Affiliations

¹ St Antonius Center for Platelet Function Research, Department of Cardiology, St Antonius Hospital Nieuwegein, the Netherlands.
² Internal Medicine, Béziers Hospital, France, Geneva Platelet Group, University of Geneva School of Medicine, Department of Internal Medicine, Rehabilitation and Geriatrics, University Hospitals of Geneva, Geneva, Switzerland.
³ Department of Medicine, Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
⁴ Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
⁵ Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, South Korea.
⁶ Heart Center Balatonfüred and Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
⁷ Stroke Pharmacogenomics and Genetics, Fundació Docència i Recerca Mútua Terrassa, Neurovascular Research Laboratory, Valle d'Hebron Hebron Institute of Research, Barcelona, Spain.
⁸ Genomic Medicine Institute, Geisinger Health System, Danville, PA, USA.
⁹ Neurovascular Research Laboratory, Vall d'Hebron Institute of Research, Barcelona, Spain.
¹⁰ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
¹¹ Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
¹² Cardiovascular Center and Cardiology Division, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
¹³ Department of Cardiology and Cardiac Catheterization Laboratory, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹⁴ University Heart Center Freiburg, Bad Krozingen, Department of Cardiology and Angiology II, Bad Krozingen, Germany.
¹⁵ Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA.
¹⁶ Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany.
¹⁷ Department of Biomedical Data Science, Stanford University, Stanford, CA, USA; Departments of Bioengineering and Genetics, Stanford University, Stanford, CA, USA; Department of Medicine, Stanford University, Stanford, CA, USA.
¹⁸ Department of Cardiology, Patras University Hospital, Patras, Greece.
¹⁹ Department of Pharmacology and Pharmacogenomics Research Center, College of Medicine, Inje University, Busan, South Korea.
²⁰ Quebec Heart and Lung Institute, Québec, Canada.
²¹ Department of Cardiology and Cardiovascular Medicine, University Hospital Tübingen, Tübingen, Germany.
²² Inova Center for Thrombosis Research and Drug Development. Inova Heart and Vascular Institute, Falls Church, VA, USA.
²³ Department of Cardiology, Swiss Cardiovascular Center Bern, Bern University Hospital, Bern, Switzerland.
²⁴ Department of Experimental and Clinical Medicine, University of Florence, Atherothrombotic Diseases Center, Careggi Hospital, Florence, Italy.
²⁵ Cardiology Unit, Azienda Ospedaliera Universitria di Ferrara, Cona (FE) and Maria Cecilia Hospital, GVM Care and Research, Cotignola, (RA), Italy.
²⁶ Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou and School of Medicine, Chang Gung University, Taoyuan City, Taiwan.
²⁷ APHP, Saint Antoine Hospital, Paris, France.
²⁸ Geneva Platelet Group, University of Geneva School of Medicine, Division of Angiology and Haemostasis, University Hospitals of Geneva, Geneva, Switzerland.
²⁹ Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
³⁰ Department of Cardiology, Medical University of Vienna, Vienna, Austria.
³¹ Sorbonne Universités, UPMC Univ Paris 06, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013 Paris, France.
³² Department of Medicine, University of Maryland, Baltimore, MD, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, Baltimore, MD.
³³ Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany; Department of Clinical Pharmacology, University Hospital, Tübingen, Germany.
³⁴ Department of Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA.
³⁵ Department of Biomedical Data Science, Stanford University, Stanford, CA, USA; Department of Medicine, Stanford University, Stanford, CA, USA.
³⁶ Department of Medicine, Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: ashuldin@som.umaryland.edu.

Abstract

Rationale: The P2Y₁₂ receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Platelet inhibition by clopidogrel shows wide interpatient variability, and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. CYP2C19 polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response.

Study design: Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics, and cardiovascular outcomes to perform candidate gene and genome-wide studies.

Results: In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate-stimulated platelet function tests included vasodilator-stimulated phosphoprotein assay, light transmittance aggregometry, and the VerifyNow P2Y₁₂ assay. A proof-of-principle analysis based on genotype data provided by each group showed a strong and consistent association between CYP2C19*2 and platelet reactivity (P value=5.1 × 10^-40).

Conclusion: The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic approaches in a large cohort of clopidogrel-treated patients to better understand the genetic basis of on-treatment response variability.

Trial registration: ClinicalTrials.gov NCT00799396.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Acute Coronary Syndrome* / diagnosis
Acute Coronary Syndrome* / drug therapy
Acute Coronary Syndrome* / mortality
Aged
Clopidogrel* / therapeutic use
Female
Genetic Association Studies
Genome-Wide Association Study*
Humans
Internationality
Male
Middle Aged
Molecular Targeted Therapy* / methods
Pharmacogenetics
Prognosis
Receptors, Purinergic P2Y12* / drug effects
Receptors, Purinergic P2Y12* / genetics
Risk Assessment
Survival Rate
Treatment Outcome

Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC)

Authors

Affiliations

Abstract

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