Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients
| Autor: | Michiaki Kubo, Tobias Geisler, Dimitrios Alexopoulos, Gian Franco Gensini, Kiyuk Chang, Jean-Luc Reny, Joshua P. Lewis, Meinrad Gawaz, Elke Schaeffeler, Kevin P. Bliden, Stefan Winter, Eun Young Kim, Ruth E. Pakyz, Paul A. Gurbel, Rossella Marcucci, Israel Fernandez-Cadenas, Joan Montaner, Nadia Paarup Dridi, Li Gong, Jae-Gook Shin, Matthias Schwab, Ryan Whaley, Jurriën M. ten Berg, John H. Cleator, Pierre Fontana, Marco Valgimigli, Russ B. Altman, Ho-Sook Kim, Joshua D. Backman, Jolanta M. Siller-Matula, Daniel Aradi, Braxton D. Mitchell, Betti Giusti, Thomas O. Bergmeijer, Kathleen A. Ryan, Alan R. Shuldiner, Ming-Shien Wen, Jean-Pierre Déry, Marylyn D. Ritchie, Teri E. Klein, Dan M. Roden, Ming Ta Michael Lee, Dietmar Trenk, Gianluca Campo, Lene Holmvang, Willibald Hochholzer |
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| Rok vydání: | 2019 |
| Předmět: |
clopidogrel
pharmacogenetics platelet aggregation medicine.medical_specialty CYP2C19 030204 cardiovascular system & hematology NO Coronary artery disease 03 medical and health sciences 0302 clinical medicine Internal medicine medicine Pharmacology (medical) CYP2C9 pharmacogenetics 030304 developmental biology clopidogrel 0303 health sciences business.industry Original Articles Odds ratio medicine.disease Clopidogrel Confidence interval platelet aggregation Pharmacogenomics Cardiology and Cardiovascular Medicine business Pharmacogenetics medicine.drug |
| Zdroj: | Eur Heart J Cardiovasc Pharmacother |
| ISSN: | 2055-6845 2055-6837 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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