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

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

doi:10.1093/ehjcvp/pvz045

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

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 HolmvangWillibald 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

Afdeling for Hjertesygdomme

79 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	European heart journal. Cardiovascular pharmacotherapy
Vol/bind	6
Udgave nummer	4
Sider (fra-til)	203-210
Antal sider	8
ISSN	2055-6837
DOI	https://doi.org/10.1093/ehjcvp/pvz045
Status	Udgivet - 2020

Adgang til dokumentet

10.1093/ehjcvp/pvz045

Andre filer og links

Link to publication in Scopus

Citationsformater

Lewis, J. P., Backman, J. D., Reny, J.-L., Bergmeijer, T. O., Mitchell, B. D., Ritchie, M. D., Déry, J.-P., Pakyz, R. E., Gong, L., Ryan, K., Kim, E.-Y., Aradi, D., Fernandez-Cadenas, I., Lee, M. T. M., Whaley, R. M., Montaner, J., Gensini, G. F., Cleator, J. H., Chang, K., ... Shuldiner, A. R. (2020). Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients. European heart journal. Cardiovascular pharmacotherapy, 6(4), 203-210. https://doi.org/10.1093/ehjcvp/pvz045

Lewis, JP, Backman, JD, Reny, J-L, Bergmeijer, TO, Mitchell, BD, Ritchie, MD, Déry, J-P, Pakyz, RE, Gong, L, Ryan, K, Kim, E-Y, Aradi, D, Fernandez-Cadenas, I, Lee, MTM, Whaley, RM, Montaner, J, Gensini, GF, Cleator, JH, Chang, K, Holmvang, L, Hochholzer, W, Roden, DM, Winter, S, Altman, R, Alexopoulos, D, Kim, H-S, Gawaz, M, Bliden, K, Valgimigli, M, Marcucci, R, Campo, G, Schaeffeler, E, Dridi, NP, Wen, M-S, Shin, JG, Fontana, P, Giusti, B, Geisler, T, Kubo, M, Trenk, D, Siller-Matula, JM, Ten Berg, JM, Gurbel, PA, Schwab, M, Klein, TE & Shuldiner, AR 2020, 'Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients', European heart journal. Cardiovascular pharmacotherapy, bind 6, nr. 4, s. 203-210. https://doi.org/10.1093/ehjcvp/pvz045

@article{2b2535f04a0a4cf484bb02c73c8c379d,

title = "Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients",

abstract = "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.",

keywords = "Clopidogrel, Pharmacogenetics, Platelet aggregation",

author = "Lewis, {Joshua P} and Backman, {Joshua D} and Jean-Luc Reny and Bergmeijer, {Thomas O} and Mitchell, {Braxton D} and Ritchie, {Marylyn D} and Jean-Pierre D{\'e}ry and Pakyz, {Ruth E} and Li Gong and Kathleen Ryan and Eun-Young Kim and Daniel Aradi and Israel Fernandez-Cadenas 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 Russ Altman and Dimitrios Alexopoulos and Ho-Sook Kim and Meinrad Gawaz and Kevin Bliden and Marco Valgimigli and Rossella Marcucci and Gianluca Campo and Elke Schaeffeler and Dridi, {Nadia P} and Ming-Shien Wen and Shin, {Jae Gook} 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 Matthias Schwab and Klein, {Teri E} and Shuldiner, {Alan R}",

year = "2020",

doi = "10.1093/ehjcvp/pvz045",

language = "English",

volume = "6",

pages = "203--210",

journal = "European heart journal. Cardiovascular pharmacotherapy",

issn = "2055-6837",

publisher = "Oxford University Press",

number = "4",

}

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

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

SN - 2055-6837

VL - 6

SP - 203

EP - 210

JO - European heart journal. Cardiovascular pharmacotherapy

JF - European heart journal. Cardiovascular pharmacotherapy

IS - 4

ER -

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

Abstract

Adgang til dokumentet

Andre filer og links

Fingeraftryk

Citationsformater