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)

for the ICPC Investigators

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)152-159
Number of pages8
JournalAmerican Heart Journal
Volume198
DOIs
Publication statusPublished - 01-04-2018

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clopidogrel
Pharmacogenetics
Genome
Genes
Blood Platelets
Platelet Function Tests
Percutaneous Coronary Intervention
Acute Coronary Syndrome

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

@article{04a6dcb594924cb1bad3576c72c3180b,
title = "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)",
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.",
author = "{for the ICPC Investigators} and Bergmeijer, {Thomas O.} and Reny, {Jean Luc} and Pakyz, {Ruth E.} and Li Gong and Lewis, {Joshua P.} and Kim, {Eun Young} and Daniel Aradi and Israel Fernandez-Cadenas and Horenstein, {Richard B.} and Lee, {Ming Ta Michael} and Whaley, {Ryan M.} and Joan Montaner and Gensini, {Gian Franco} and Cleator, {John H.} and Kiyuk Chang and Lene Holmvang and Willibald Hochholzer and Roden, {Dan M.} and Stefan Winter and Altman, {Russ B.} and Dimitrios Alexopoulos and Kim, {Ho Sook} and D{\'e}ry, {Jean Pierre} and Meinrad Gawaz and Kevin Bliden and Marco Valgimigli and Rossella Marcucci and Gianluca Campo and Elke Schaeffeler and Dridi, {Nadia P.} and Wen, {Ming Shien} and Shin, {Jae Gook} and Tabassome Simon and Pierre Fontana and Betti Giusti and Tobias Geisler and Michiaki Kubo and Dietmar Trenk and Siller-Matula, {Jolanta M.} and {ten Berg}, {Jurri{\"e}n M.} and Gurbel, {Paul A.} and Hulot, {Jean Sebastien} and Mitchell, {Braxton D.} and Matthias Schwab and Ritchie, {Marylyn De Riggi} and Klein, {Teri E.} and Michiaki Kubo",
year = "2018",
month = "4",
day = "1",
doi = "10.1016/j.ahj.2017.12.010",
language = "English",
volume = "198",
pages = "152--159",
journal = "American Heart Journal",
issn = "0002-8703",
publisher = "Mosby Inc.",

}

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 - for the ICPC Investigators

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 De Riggi

AU - Klein, Teri E.

AU - Kubo, Michiaki

PY - 2018/4/1

Y1 - 2018/4/1

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.

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U2 - 10.1016/j.ahj.2017.12.010

DO - 10.1016/j.ahj.2017.12.010

M3 - Article

C2 - 29653637

AN - SCOPUS:85040931385

VL - 198

SP - 152

EP - 159

JO - American Heart Journal

JF - American Heart Journal

SN - 0002-8703

ER -