CYP2C19 genotype: a moving target?

Purpose: Cytochrome P450 2C19 metabolizes many important medications.  Some variants of CYP2C19 will result in increased or decreased metabolism.  Recently, a variant allele (CYP2C19*17) associated with increased gene transcription and thus ultra rapid metabolism of CYP2C19 substrates was discovered.   The aim of this study was to investigate the CYP2C19*17 allelic frequency and recalculate previously reported frequencies of the CYP2C19*1 allele. 

Methods: Seventy-nine patients that had already been genotyped for CYP2C19 participated in the study.  Laboratory specimens were analyzed using the Applied Biosystems Taqman Drug Metabolism Genotyping Assays, a real-time PCR based genotyping platform which uses 5’ nuclease chemistry for amplifying and detecting specific polymorphisms in purified genomic DNA samples.  Prevalence of genotypes, alleles, and predicted phenotypes were determined.  Distribution of observed genotypes according to ethnicity was documented.  Genotypes using the expanded assay were compared to previous results. 

Results: The CYP2C19*17 allelic frequency was 24.7%.  Genotyping CYP2C19*17 changed our frequency of extensive metabolizers from 74.7% (defined as CYP2C19*1/*1) to 64.6% (defined as CYP2C19*1/*1 or CYP2C19*1/*17), reclassifying 10.1% as ultra rapid metabolizers (defined as CYP2C19*17/*17).  Distribution of CYP2C19*17 alleles was consistent with known frequencies in the general population.

Conclusion: As a result of CYP2C19 testing, individuals with genotypes associated with a higher risk of adverse events or a risk of lack of therapeutic response can be identified, and an alternative strategy can be instituted.  Several studies have already reported the functional effect of CYP2C19*17 may be clinically important.  Our study highlights the need for reassessment of CYP2C19 allelic frequencies in view of the role CYP2C19*17 may have in predicting clinical outcome for drugs metabolized via this pathway.