CYP2C19

Cytochrome P450 family 2 subfamily C member 19 (CYP2C19) is a very important gene in the field of pharmacogenomics. It encodes a cytochrome P450 enzyme that metabolises many commonly prescribed medicines, including antidepressants, proton pump inhibitors and clopidogrel, an antiplatelet drug. CYP2C19 is highly polymorphic: 39 haplotypes have been characterised by their impact on drug metabolism. This CYP2C19 genetic heterogeneity is associated with significant pharmacokinetic variation between individuals, which impacts on drug efficacy and the risk of adverse effects.

• The Human Genome Organisation Gene Nomenclature Committee-approved name for this gene is cytochrome P450 family 2 subfamily C member 19 (CYP2C19).
• CYP2C19 is located at chromosome 10q23.33, within a cluster of four cytochrome P450 genes (CYP2C8, CYP2C9, CYP2C18 and CYP2C19).
• CYP2C19 contains nine exons, spanning 92,867 base pairs of DNA.
• It is a member of a supergene family, which encodes the cytochrome P450 (CYP) enzymes. CYP enzymes metabolise endogenous and exogenous compounds.

• CYP2C19 is an inducible phase-one enzyme that is mainly expressed in the liver.
• Drug-drug interactions (with inhibitors and inducers for CYP2C19) are of particular concern in the elderly, in whom polypharmacy is common.

Like other CYP genes, genetic variation in CYP2C19 and its variable hepatic expression contributes to inter-individual variability in the metabolism of the CYP2C19 enzyme’s substrates. The plasma concentration of a drug (or its metabolites) can vary significantly between patients because of genetically determined heterogeneity in enzyme activity; this can be predicted by genomic tests for functionally important variants. The relevant variants include amino acid-changing single nucleotide variants, splicing variants and deletions. New allelic variants continue to be identified.

Functional haplotypes can be detected to inform prescribing decisions, which are classified using star (*) allele nomenclature, with CYP2C19*1 being the reference allele. A full list of variants that define each star allele is curated and published by PharmGKB. Individuals may be classified depending on their ability to metabolise CYP2C19 substrates, and classification is based on the highest-functioning CYP2C19 allele in the individual’s genotype (also referred to as a diplotype). Alleles are described as having no function, decreased function, normal function, uncertain function or increased function, and the combination of alleles present in a genotype allows for prediction of an individual’s metaboliser phenotype.

There are global differences in CYP2C19 allele frequency between and within populations. For example, about 20%–30% of White individuals in the UK have at least one loss-of-function variant in CYP2C19, which increases to about 50%–60% in East Asian populations. The frequency of specific alleles within populations can inform the utility of pharmacogenomic testing; however, clinical recommendations are based on an individual’s metaboliser phenotype.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published guidelines based on clinically actionable CYP2C19 genotypes for the following drugs:

• clopidogrel;
• proton pump inhibitors;
• selective serotonin reuptake inhibitors;
• tricyclic antidepressants; and
• voriconazole.

Note that, at the time of writing, CYP2C19-genotype-informed prescribing is not routinely adopted within the NHS.

For functional classification, there are five categories to describe an individual’s CYP2C19 metaboliser phenotype:

• poor;
• intermediate;
• normal;
• rapid; and
• ultra-rapid.

An individual’s predicted phenotype is based on the two alleles of their genotype (diplotype). For example, an individual who has the CYP2C19*6/*7 genotype has the CYP2C19*6 allele in one copy of the gene and the CYP2C19*7 allele in the other. Both of these alleles result in a non-functional enzyme, which means that this individual is predicted to be a poor metaboliser for CYP2C19 substrates. They may be at high risk of experiencing adverse reactions or poor response to medications that are metabolised by CYP2C19, meaning that dose adjustments or alternative therapy may be necessary. Please consult a clinical pharmacist for more information about how CYP2C19 metabolic status influences drug selection and dosing.

In summary, the risk of adverse reaction to certain commonly prescribed medicines could be reduced by interpreting the patient’s metaboliser status for particular CYP2C19 genetic variants and modifying prescribing decisions accordingly. Published guidelines and curated databases in the resources list below can be used to understand the gene nomenclature and how to apply genomic testing in treatment decisions. For more information about genomic testing, see Results: Patient with a known CYP2C19 genotype and coronary artery disease requiring clopidogrel.

For clinicians

• Clinical Pharmacogenetics Implementation Consortium (CPIC)
• Pharmacogene Variation Consortium (PharmVar)
• PharmGKB: Gene-specific information tables for CYP2C19
• PHG Foundation: Explaining pharmacogenomics (video, two minutes 16 seconds)

References:

• Botton MR, Whirl-Carrillo M, Del Tredici AL and others. ‘PharmVar GeneFocus: CYP2C19’. Clinical Pharmacology & Therapeutics 2021: volume 109, issue 2, pages 352–366. DOI: 10.1002/cpt.1973
• Ingelman-Sundberg M, Sim SC, Gomez A and others. ‘Influence of cytochrome P450 polymorphisms on drug therapies: Pharmacogenetic, pharmacoepigenetic and clinical aspects’. Pharmacology & Therapeutics 2007: volume 116, issue 3, pages 496–526. DOI: 1016/j.pharmthera.2007.09.004
• Scott SA, Sangkuhl K, Shuldiner AR and others. ‘PharmGKB summary: Very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 19’. Pharmacogenetics and Genomics 2012: volume 22, issue 2, pages 159–165. DOI: 1097/FPC.0b013e32834d4962