TY - JOUR

T1 - 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)

AU - Bergmeijer, Thomas O

AU - Reny, Jean-Luc

AU - Pakyz, Ruth E

AU - Gong, Li

AU - Lewis, Joshua P

AU - Kim, Eun-Young

AU - Aradi, Daniel

AU - Fernandez-Cadenas, Israel

AU - Horenstein, Richard B

AU - Lee, Ming Ta Michael

AU - Whaley, Ryan M

AU - Montaner, Joan

AU - Gensini, Gian Franco

AU - Cleator, John H

AU - Chang, Kiyuk

AU - Holmvang, Lene

AU - Hochholzer, Willibald

AU - Roden, Dan M

AU - Winter, Stefan

AU - Altman, Russ B

AU - Alexopoulos, Dimitrios

AU - Kim, Ho-Sook

AU - Déry, Jean-Pierre

AU - Gawaz, Meinrad

AU - Bliden, Kevin

AU - Valgimigli, Marco

AU - Marcucci, Rossella

AU - Campo, Gianluca

AU - Schaeffeler, Elke

AU - Dridi, Nadia P

AU - Wen, Ming-Shien

AU - Shin, Jae Gook

AU - Simon, Tabassome

AU - Fontana, Pierre

AU - Giusti, Betti

AU - Geisler, Tobias

AU - Kubo, Michiaki

AU - Trenk, Dietmar

AU - Siller-Matula, Jolanta M

AU - Ten Berg, Jurriën M

AU - Gurbel, Paul A

AU - Hulot, Jean-Sebastien

AU - Mitchell, Braxton D

AU - Schwab, Matthias

AU - Ritchie, Marylyn DeRiggi

AU - Klein, Teri E

AU - Shuldiner, Alan R

AU - ICPC Investigators

N1 - Copyright © 2017 Elsevier Inc. All rights reserved.

PY - 2018/4

Y1 - 2018/4

N2 - 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.

AB - 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.

KW - Acute Coronary Syndrome/diagnosis

KW - Aged

KW - Clopidogrel/therapeutic use

KW - Female

KW - Genetic Association Studies

KW - Genome-Wide Association Study

KW - Humans

KW - Internationality

KW - Male

KW - Middle Aged

KW - Molecular Targeted Therapy/methods

KW - Pharmacogenetics

KW - Prognosis

KW - Receptors, Purinergic P2Y12/drug effects

KW - Risk Assessment

KW - Survival Rate

KW - Treatment Outcome

U2 - 10.1016/j.ahj.2017.12.010

DO - 10.1016/j.ahj.2017.12.010

M3 - Review

C2 - 29653637

VL - 198

SP - 152

EP - 159

JO - American Heart Journal

JF - American Heart Journal

SN - 0002-8703

ER -