1. 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)
- Author
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Dan M. Roden, Marylyn D. Ritchie, Jae-Gook Shin, Braxton D. Mitchell, Teri E. Klein, Gian Franco Gensini, Jurriën M. ten Berg, Pierre Fontana, Lene Holmvang, Israel Fernandez-Cadenas, Willibald Hochholzer, Stefan Winter, Tabassome Simon, Ruth E. Pakyz, Paul A. Gurbel, Richard B. Horenstein, Ming-Shien Wen, Tobias Geisler, John H. Cleator, Marco Valgimigli, Ho-Sook Kim, Jean-Sébastien Hulot, Jolanta M. Siller-Matula, Dietmar Trenk, Gianluca Campo, Michiaki Kubo, Elke Schaeffeler, Nadia Paarup Dridi, Ming Ta Michael Lee, Li Gong, Joshua P. Lewis, Jean-Pierre Déry, Rossella Marcucci, Kiyuk Chang, Meinrad Gawaz, Kevin P. Bliden, Alan R. Shuldiner, Daniel Aradi, Thomas O. Bergmeijer, Betti Giusti, Russ B. Altman, Dimitrios Alexopoulos, Matthias Schwab, Ryan Whaley, Jean-Luc Reny, Joan Montaner, Eun Young Kim, Reny, Jean-Luc, Fontana, Pierre, Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Oncology ,Male ,Candidate gene ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,Internationality ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Genome-wide association study ,030204 cardiovascular system & hematology ,Cardiovascular Medicine ,MESH: Risk Assessment ,MESH: Receptors, Purinergic P2Y12 ,0302 clinical medicine ,P2Y12 ,MESH: Molecular Targeted Therapy ,Receptors ,Medicine ,030212 general & internal medicine ,Molecular Targeted Therapy ,MESH: Treatment Outcome ,MESH: Genetic Association Studies ,Cardiology, Cardiovascular Medicine ,MESH: Aged ,ddc:616 ,Acute Coronary Syndrome/diagnosis/drug therapy/mortality ,MESH: Middle Aged ,Purinergic P2Y12/drug effects/genetics ,Middle Aged ,Clopidogrel ,Prognosis ,Receptors, Purinergic P2Y12 ,3. Good health ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,Survival Rate ,Treatment Outcome ,Female ,Cardiology and Cardiovascular Medicine ,medicine.drug ,circulatory and respiratory physiology ,Acute coronary syndrome ,medicine.medical_specialty ,MESH: Survival Rate ,Cardiology ,MESH: Pharmacogenetics ,CYP2C19 ,Clopidogrel/therapeutic use ,Risk Assessment ,MESH: Prognosis ,Article ,NO ,03 medical and health sciences ,Internal medicine ,Humans ,cardiovascular diseases ,Acute Coronary Syndrome ,Genetic Association Studies ,Aged ,MESH: Humans ,business.industry ,MESH: Clopidogrel ,medicine.disease ,Genome-wide association approach, candidate gene approaches, clopidogrel, efficacy, pharmacodynamic, clinical end points, International Clopidogrel Pharmacogenomics Consortium (ICPC), Cardiovascular Medicine ,MESH: Acute Coronary Syndrome ,MESH: Male ,Pharmacogenetics ,Pharmacogenomics ,MESH: Genome-Wide Association Study ,ddc:618.97 ,MESH: Internationality ,business ,MESH: Female ,Molecular Targeted Therapy/methods ,Genome-Wide Association Study - Abstract
RATIONALE: The P2Y(12) receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention or ischemic stroke. Platelet inhibition by clopidogrel shows wide inter-patient 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 association 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 (ADP) stimulated platelet function tests included Vasodilator-Stimulated Phosphoprotein (VASP) assay, Light Transmittance Aggregometry (LTA) and the VerifyNow P2Y(12) 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 techniques in a large cohort of clopidogrel-treated patients in order to better understand the genetic basis of on-treatment response variability.
- Published
- 2017