Pharmacogenetic testing of CYP2D6, CYP2C19 and CYP2C9 in Denmark: Agreement between publicly funded genotyping tests and the subsequent phenotype classification

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The cytochrome P450 (CYP) enzyme family catalyses the metabolism of approximately 80% of all medications.1, 2 Many genes encoding the CYP enzymes exhibit high levels of polymorphism that affect their expression and activity. The most frequent and clinically important variations exist within the genes CYP2D6, CYP2C19 and CYP2C9.1 CYP2D6, the most extensively studied drug-metabolizing enzyme, has over 100 allelic variants and is responsible for metabolizing about 25% of all marketed medications.1, 3 CYP2C19 and CYP2C9 are collectively responsible for metabolizing about 20% of medications. It is estimated that 74%–97% of Caucasian individuals possess at least one genetic variation in the CYP gene, potentially affecting metabolism for about one quarter of all prescribed medications.4 Testing for this genetic variation can help identify individuals for whom medication safety and efficacy can be improved through dose adjustment.1

Pharmacogenetic (PGx) testing assesses genetic variation by identifying a patient's genotype and assigning a predicted phenotype. The predicted phenotype of an inherited allele can be classified as loss of function, decreased function, normal function or increased function.3 Numerous PGx tests have been developed for both public and private use. The evidence for whether these tests actually improve treatment outcomes is controversial, but a large implementation study recently showed that pre-emptive PGx testing may reduce the incidence of adverse reactions.5 PGx tests are normally based on genotyping panels with predefined alleles, but variations in these panels between PGx providers and in the approach for genotype-to-phenotype translation can result in conflicting recommendations.6, 7 Current guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) recommend classifying phenotypes into four, five and three categories for CYP2D6, CYP2C19 and CYP2C9, respectively.8

Despite these recommendations, a recent study by Bousman and Dunlop found substantial variation in reported genotype, phenotype and resulting medication recommendations between four commercial PGx tests. Based on this, the authors called for standardization of PGx tests and development of medication guidelines specifying which alleles should be included in the PGx test.7 In response, recommendation guidelines for selection of relevant CYP2D6 alleles for PGx testing were published in 2021.9

In Denmark, approximately 800 PGx tests of CYP2D6, CYP2C19 and CYP2C9 are conducted annually across three public laboratories. Evaluation of the agreement in determined genotype and the subsequent phenotype assignment is essential for the credibility of PGx testing to ensure that clinicians will utilize this approach. The objectives of this pilot study were to (1) assess how well the three laboratories agreed on genotypes, (2) assess how well the three laboratories agreed on genotype-to-phenotype translation and (3) identify potential causes of observed discrepancies in genotypes and genotype-to-phenotype translation between the three laboratories.
Original languageEnglish
JournalBasic and Clinical Pharmacology and Toxicology
Issue number5
Pages (from-to)756-763
Number of pages8
Publication statusPublished - 2024

    Research areas

  • CYP2C19, CYP2C9, CYP2D6, genotype, genotype-phenotype association, pharmacogenomics, phenotype

ID: 385221636