Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update

Abstract

CPIC UPDATETable 1 Assignment of predicted CYP2C19 phenotype based on genotype Predicted phenotype Genotype Examples of CYP2C19 diplotypes a CYP2C19 ultrarapid metabolizer An individual carrying two increased function alleles *17/*17 CYP2C19 rapid metabolizer An individual carrying one normal function allele and one increased function allele *1/*17 CYP2C19 normal metabolizer An individual carrying two normal function alleles *1/*1 CYP2C19 likely intermediate metabolizer b An individual carrying one normal function allele and one decreased function allele or one increased function allele and one decreased function allele or two decreased function alleles *1/*9, *9/*17, *9/*9 CYP2C19 intermediate metabolizer An individual carrying one normal function allele and one no function allele or one increased function allele and one no function allele *1/*2, *1/*3, *2/*17, *3/*17 CYP2C19 likely poor metabolizer b An individual carrying one decreased function allele and one no function allele *2/*9, *3/*9 CYP2C19 poor metabolizer An individual carrying two no function alleles *2/*2, *3/*3, *2/*3 Indeterminate metabolizer An individual carrying one or two uncertain function alleles *1/*12, *2/*12, *12/*14 a Please refer to the CYP2C19 Diplotype-Phenotype Table online for a complete list. For allele functions and population-specific allele and phenotype frequencies, please refer to the CYP2C19 Allele Functionality Table and the CYP2C19 Allele Frequency Table online. 8,9 bThere are limited data to characterize the function of decreased function alleles.

Ethnic Diversity and Warfarin Pharmacogenomics

“…Clopidogrel is a thienopyridine pro-drug that is metabolized in the liver to an active metabolite that inhibits platelet aggregation ( Lamoureux et al, 2017 ; Lee et al, 2022 ). The key metabolizing enzyme is Cytochrome P450 isoform 2C19 (CYP2C19), coded for by the CYP2C19 gene, with null function alleles such as CYP2C19*2 (rs4244285, splicing defect with appearance of a stop codon) and CYP2C19*3 (rs4986893, nonsense variant with a premature stop codon) being associated with slow metabolizer phenotypes (reduced therapeutic efficacy/poor response to clopidogrel as less clopidogrel is transformed to its active metabolite).…”

“…The key metabolizing enzyme is Cytochrome P450 isoform 2C19 (CYP2C19), coded for by the CYP2C19 gene, with null function alleles such as CYP2C19*2 (rs4244285, splicing defect with appearance of a stop codon) and CYP2C19*3 (rs4986893, nonsense variant with a premature stop codon) being associated with slow metabolizer phenotypes (reduced therapeutic efficacy/poor response to clopidogrel as less clopidogrel is transformed to its active metabolite). On the other hand, CYP2C19*17 (rs12248560, gene promoter variant) increases gene transcription and protein expression which can lead to excessive inhibition of platelet aggregation and increased risk of haemorrhagic events in clopidogrel-treated carriers of this allele ( Lamoureux et al, 2017 ; Lee et al, 2022 ). Due to differences in MAFs for these SNPs [ CYP2C19*2 African = 0.17, American = 0.11, East Asian = 0.31, European = 0.15, South Asian = 0.36; CYP2C19*3 East Asian = 0.06, South Asian = 0.01, Other ∼0.00; and, CYP2C19*17 African = 0.24, American = 0.12, East Asian = 0.02, European = 0.22, South Asian = 0.14 ( Genomes Project et al, 2015 )], the importance of these CYP2C19 variants will differ from population to population, which also means that studies conducted in one population may not be applicable to another.…”

Impact of the ABCD‐GENE Score on Clopidogrel Clinical Effectiveness after PCI: A Multi‐Site, Real‐World Investigation

“…Patients carrying a no function allele were assigned the CYP2C19 poor metabolizer (PM; 2 no function alleles) or intermediate metabolizer (IM; one no function allele) phenotype, consistent with Clinical Pharmacogenetics Implementation Consortium guidelines. 16 At each institution, alternative antiplatelet therapy with prasugrel or ticagrelor was recommended for CYP2C19 IMs and PMs, in the absence of contraindications, whereas no prescribing recommendations were made for those without a no function allele. 34 The ultimate prescribing decision was left to the clinician's discretion, and ~ 45% of IMs and PMs were treated with clopidogrel across sites.…”

“…24,28 Given evidence that CYP2C19 genotype influences the effectiveness of clopidogrel, but not prasugrel or ticagrelor, pharmacogenetic guidelines recommend prasugrel or ticagrelor for CYP2C19 IMs and PMs in the absence of contraindications. 16 Similarly, the US Food and Drug Administration-approved clopidogrel labeling recommends alternative therapy in PMs, with recommendations for alternative therapy expanded to IMs in their Table of Pharmacogenetic Associations. 39,40 Clinical trials and observational studies have examined outcomes with guided approaches to the selection of P2Y 12 inhibitor therapy, using either genetic or platelet function testing.…”

“…14,15 Approximately 30% of the US population carries at least one CYP2C19 no function allele. 16 Among clopidogreltreated patients, no function allele carriers have lower concentrations of the active clopidogrel metabolite, higher platelet reactivity and HPR rates, and are at increased risk for cardiovascular events after PCI compared with those without a no function allele. 17,18 In addition to CYP2C19 genotype, clinical factors, including older age, higher body mass index (BMI), chronic kidney disease (CKD), and diabetes mellitus (DM), contribute to HPR and are associated with reduced clopidogrel effectiveness.…”