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.

Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium

“…Lead investigators were invited to share DNA samples, platelet reactivity test results, patient characteristics, and cardiovascular outcomes to perform candidate gene and GWAS. 22 To date, 17 sites from 13 countries have joined the ICPC, contributing data representing 8,829 clopidogrel-exposed patients. Of those patients, a DNA sample was available in 5,119 patients, a DNA sample and platelet reactivity data in 4,511 patients, and in 2,844 patients a DNA sample, platelet reactivity data, and clinical outcome data were available.…”

Platelet Function Test Use for Patients with Coronary Artery Disease in the Early 2020s

“…These data were further supported by a study of 760 cardiovascular patients treated with clopidogrel; it found that the CYP2C19*2 genotype accounted for only 5.2% of the platelet reactivity phenotype [31]. The genetic background of this variability is indeed probably multigenic, as shown by a recent collaborative study [32].…”

“…It has several key advantages over PFTs, including quickly available, unequivocal results using current point-of-care assays, the absence of inter-individual variability, and, most importantly, there being no need to potentially challenge the patient with an antiplatelet drug for several days before a PFT. However, and as mentioned above, the currently available knowledge of the genetic background governing antiplatelet drug pharmacodynamics only explains between 3.5% and 12% of clopidogrel response [29][30][31][32], and the present genetic panel available poorly reflects the drug's pharmacodynamics. Nevertheless, several trials have investigated the clinical impact of a strategy based on genetics to tailor antiplatelet drug treatment in de-escalation settings.…”

microRNA-605 rs2043556 polymorphisms affect clopidogrel therapy through modulation of CYP2B6 and P2RY12 in acute coronary syndrome patients

“…Furthermore, we should detect the concentration of clopidogrel and its active metabolite to assess CYP2B6 activity. Since several polymorphisms impacted the clinical outcomes of clopidogrel therapy in the present study, a strategy utilizing a pharmacogenomic polygenic response score is needed to predict cardiovascular events in the future [44].…”