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 - Shuldiner, Alan R.
N1 - Funding Information:
The Taiwanese cohort research was supported by grants to Chao-Yung Wang from the National Health Research Institute (NHRI-EX100-9925SC), the National Science Council (98-2314-B-182A-082-MY3), and the Chang Gung Memorial Hospital (CMRPG391861) and to Ming-Shien Wen from NRPB (101TM1033) and the Chang Gung Memorial Hospital (CMRPG3A1071). The Korean cohort was supported by a grant of Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea (HI15C1537).
Funding Information:
The Taiwanese cohort research was supported by grants to Chao-Yung Wang from the National Health Research Institut e ( NHRI-EX100-9925SC ), the National Science Council ( 98-2314-B-182A-082-MY3 ), and the Chang Gung Memorial Hospital ( CMRPG391861 ) and to Ming-Shien Wen from NRPB ( 101TM1033 ) and the Chang Gung Memorial Hospital ( CMRPG3A1071 ). The Korean cohort was supported by a grant of Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea ( HI15C1537 ).
Funding Information:
The ICPC research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) under Award Number U01HL105198 and NIH National Institute of General Medical Sciences grant R24GM61374 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Genome-wide SNP genotyping is supported by the Pharmacogenomics Research Network & CGM Global Alliance. P-STAR is funded by NIH grant HL065962 . I. F. C. thanks Dr Christina-Gallego-Fabrega for compiling clinical data and performing genotyping. J. L. R. recognizes Dr Christophe Combescure's contributions to the analysis plan. The authors thank Ankita Parihar, John Wallace, and Shefali Setia for data QC and analyses performed. The authors gratefully acknowledge the editorial and data contributions of Prof Bernd Jilma, principal investigator of the PEGASUS-PCI study.
Funding Information:
Dr Simon reports grants from AstraZeneca, Daiichi-Sankyo, Eli-Lilly, GSK, MSD, Novartis, and Sanofi and personal fees from Board membership, consultancy, or lecture from AstraZeneca, Astellas, Bayer, BMS, Lilly, MSD, Novartis, and Sanofi outside the submitted work. Dr Hochholzer reports grants from German Heart Foundation and personal fees from AstraZeneca, The Medicines Company, Boehringer Ingelheim, and Daiichi Sankyo outside the submitted work. Dr Aradi reports personal fees from Roche Diagnostics, Verum Diagnostica, DSI/Lilly, AstraZeneca, Krka, Pfizer, Bayer AG, and MSD Pharma outside the submitted work. Drs Schwab, Schaeffeler, Winter, and Geisler are supported by the DFG Germany (grant number SCHW858/1-2) and in part by the EU Horizon 2020 UPGx grant (668353) and the Robert Bosch Stiftung Stuttgart, Germany. Dr ten Berg reports receiving fees for board membership from AstraZeneca; consulting fees from AstraZeneca, Eli Lilly, and Merck; and lecture fees from Daiichi Sankyo and Eli Lilly, AstraZeneca, Sanofi and Accumetrics outside the submitted work. Dr Altman holds stock in Personalis Inc and 23andMe, and is a paid advisor for Karius. Dr Alexopoulos reports receiving advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim, and the Medicines Company and lecture fees from AstraZeneca outside the submitted work. Dr Reny reports an unrestricted research grant from Daiichi-Sankyo and a travel grant from Bayer. Dr Bergmeijer received a personal grant from the St Antonius Research Fund. Dr Shuldiner is an employee of Regeneron Pharmaceuticals, Inc.
Publisher Copyright:
© 2017 Elsevier Inc.
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.
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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 -