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Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients

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  • Joshua P Lewis
  • Joshua D Backman
  • Jean-Luc Reny
  • Thomas O Bergmeijer
  • Braxton D Mitchell
  • Marylyn D Ritchie
  • Jean-Pierre Déry
  • Ruth E Pakyz
  • Li Gong
  • Kathleen Ryan
  • Eun-Young Kim
  • Daniel Aradi
  • Israel Fernandez-Cadenas
  • Ming Ta Michael Lee
  • Ryan M Whaley
  • Joan Montaner
  • Gian Franco Gensini
  • John H Cleator
  • Kiyuk Chang
  • Lene Holmvang
  • Willibald Hochholzer
  • Dan M Roden
  • Stefan Winter
  • Russ Altman
  • Dimitrios Alexopoulos
  • Ho-Sook Kim
  • Meinrad Gawaz
  • Kevin Bliden
  • Marco Valgimigli
  • Rossella Marcucci
  • Gianluca Campo
  • Elke Schaeffeler
  • Nadia P Dridi
  • Ming-Shien Wen
  • Jae Gook Shin
  • Pierre Fontana
  • Betti Giusti
  • Tobias Geisler
  • Michiaki Kubo
  • Dietmar Trenk
  • Jolanta M Siller-Matula
  • Jurriën M Ten Berg
  • Paul A Gurbel
  • Matthias Schwab
  • Teri E Klein
  • Alan R Shuldiner
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AIMS : Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial.

METHODS AND RESULTS : We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10-54; CES1 G143E, P = 1.3 × 10-16; CYP2C19*17, P = 9.5 × 10-10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10-4; CYP2B6 516 G > T, P = 1.0 × 10-3; CYP2C9*2, P = 1.2 × 10-3; and CYP2C9*3, P = 1.5 × 10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14-2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35-14.27, P = 0.01) compared to patients who carried six or fewer of these alleles.

CONCLUSION : Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.

Original languageEnglish
JournalEuropean heart journal. Cardiovascular pharmacotherapy
Volume6
Issue number4
Pages (from-to)203-210
Number of pages8
ISSN2055-6837
DOIs
Publication statusPublished - 2020

Bibliographical note

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.

ID: 59123249