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