Global distribution of CYP2C19 risk phenotypes affecting safety and effectiveness of medications

Abstract

Genetic variability of CYP2C19 may affect safety or efficacy of many clinically important medications as outlined in the clinical pharmacogenetics implementation consortium (CPIC) dosing guidelines. To determine the predictive prevalence of high-risk phenotypes due to CYP2C19 genetic variants collectively in the world population and to establish a correlation how the identified high-risk phenotypes may affect safety or effectiveness of drugs, this study was conducted. Frequency of CYP2C19*2, *3 and *17 alleles were obtained from 1000 Genomes project Phase III in line with Fort Lauderdale principles. Phenotypes were assigned using international standardized consensus terms based on the carrier of characteristics alleles. Association of predicted high-risk phenotypes with the safety or effectiveness of medications was gained from CPIC dosing guidelines. Ultrarapid and poor metabolizers were considered as being as high-risk phenotypes for at least ten clinically important medications. Meta-analysis of the prevalence of high-risk phenotypes showed that it was statistically significant (p<0.0001) in different ethnic groups with pooled prevalence of 27.4% (95% CI 18–37%). The present study suggests that African (37.2; 95% CI 34–41%) and European (35.4; 95% CI 31–40%) population are being at particularly higher risk of either sub therapeutic drug responses or toxicities due to combined effects of CYP2C19*2, *3 and *17 variants. Large scale clinical studies are warranted to assess clinical outcomes of these medications considering CYP2C19 pharmacogenomics effects.

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Fig. 1: Frequency of CYP2C19*1, CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles in 26 world population comprising 2504 participants participated in the 1000 Genomes Project.
Fig. 2: Prevalence of CYP2C19 genetic polymorphisms.
Fig. 3: Predicted prevalence of different phenotypes of different population participated in 1000 Genomes project.
Fig. 4: Prevalence of risk phenotypes.
Fig. 5: PharmGKB evidence levels of drugs affected by CYP2C19*2, *3 or *17 genetic variability.
Fig. 6: Drug labels information.

Data availability

The datasets generated during and/or analysed during this current study are available in the 1000 Genomes data repository (https://www.internationalgenome.org/).

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Correspondence to Mohitosh Biswas.

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Biswas, M. Global distribution of CYP2C19 risk phenotypes affecting safety and effectiveness of medications. Pharmacogenomics J (2020). https://doi.org/10.1038/s41397-020-00196-3

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