TY - JOUR
T1 - Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients
AU - Lewis, Joshua P
AU - Backman, Joshua D
AU - Reny, Jean-Luc
AU - Bergmeijer, Thomas O
AU - Mitchell, Braxton D
AU - Ritchie, Marylyn D
AU - Déry, Jean-Pierre
AU - Pakyz, Ruth E
AU - Gong, Li
AU - Ryan, Kathleen
AU - Kim, Eun-Young
AU - Aradi, Daniel
AU - Fernandez-Cadenas, Israel
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
AU - Alexopoulos, Dimitrios
AU - Kim, Ho-Sook
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 - 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 - Schwab, Matthias
AU - Klein, Teri E
AU - Shuldiner, Alan R
N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Clopidogrel
KW - Pharmacogenetics
KW - Platelet aggregation
UR - http://www.scopus.com/inward/record.url?scp=85088267672&partnerID=8YFLogxK
U2 - 10.1093/ehjcvp/pvz045
DO - 10.1093/ehjcvp/pvz045
M3 - Journal article
C2 - 31504375
VL - 6
SP - 203
EP - 210
JO - European Heart Journal - Cardiovascular Pharmacotherapy
JF - European Heart Journal - Cardiovascular Pharmacotherapy
SN - 2055-6837
IS - 4
ER -