Pharmacogenomic Impact of CYP2C19 Variation on Clopidogrel Therapy in Precision Cardiovascular Medicine

Abstract

Variability in response to antiplatelet therapy can be explained in part by pharmacogenomics, particularly of the CYP450 enzyme encoded by CYP2C19. Loss-of-function and gain-of-function variants help explain these interindividual differences. Individuals may carry multiple variants, with linkage disequilibrium noted among some alleles. In the current pharmacogenomics era, genomic variation in CYP2C19 has led to the definition of pharmacokinetic phenotypes for response to antiplatelet therapy, in particular, clopidogrel. Individuals may be classified as poor, intermediate, extensive, or ultrarapid metabolizers, based on whether they carry wild type or polymorphic CYP2C19 alleles. Variant alleles differentially impact platelet reactivity, concentration of plasma clopidogrel metabolites, and clinical outcomes. Interestingly, response to clopidogrel appears to be modulated by additional factors, such as sociodemographic characteristics, risk factors for ischemic heart disease, and drug-drug interactions. Furthermore, systems medicine studies suggest that a broader approach may be required to adequately assess, predict, preempt, and manage variation in antiplatelet response. Transcriptomics, epigenomics, exposomics, miRNAomics, proteomics, metabolomics, microbiomics, and mathematical, computational, and molecular modeling should be integrated with pharmacogenomics for enhanced prediction and individualized care. In this review of pharmacogenomic variation of CYP450, a systems medicine approach is described for tailoring antiplatelet therapy in clinical practice of precision cardiovascular medicine.

Clopidogrel‐associated genetic variants on inhibition of platelet activity and clinical outcome for acute coronary syndrome patients

“…5 As suggested by the clinical practice guidelines from the European Society of Cardiology (ESC), 3 dual antiplatelet therapy could prevent the re-infarction in ACS patients who have undergone percutaneous coronary intervention (PCI). Clopidogrel is the most widely used P2Y 12 receptor antagonist irreversibly inhibiting adenosine diphosphate (ADP) binding to its receptor 6 and it plays an important role in the inhibition of platelet aggregation (IPA). 7 Clopidogrel transforms into its active metabolites under the catalysation of cytochrome P450 (CYP).…”

The Role of CYP450 Drug Metabolism in Precision Cardio-Oncology

“…In humans, more than 100 collective genes and pseudogenes encode over 50 CYP450 enzymes. CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 metabolize over 90% of the substrate drugs and are the most extensively studied CYP450 enzymes [1][2][3]7] (Table 1). The pie chart depicts the various P450 isoforms, the percentage of clinically used drugs metabolized by the isoform and factors inducing or inhibiting the respective P450 enzyme, thereby influencing variability.…”

“…In humans, more than 100 collective genes and pseudogenes encode over 50 CYP450 enzymes. CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 metabolize over 90% of the substrate drugs and are the most extensively studied CYP450 enzymes [1][2][3]7] (Table 1).…”

“…This has direct clinical applicability. This can be illustrated by examining two CYP450 enzymes relevant to Cardio-Oncology-CYP2C19 and CYP2D6 [7,16,68].…”

“…Over 50 CYP2C19 genomic variants have been identified [7]. The CYP2C19 gene is located on chromosome 10q24.1q24.3, is composed of nine exons and produces a medium-sized protein (55.93 kDa) from 490 amino acids [7].…”