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.