Abstract
CYP2C19 and CYP2D6 are important drug-metabolizing enzymes that are involved in the metabolism of around 30% of all medications. Importantly, the corresponding genes are highly polymorphic and these genetic differences contribute to interindividual and interethnic differences in drug pharmacokinetics, response, and toxicity. In this study we systematically analyzed the frequency distribution of clinically relevant CYP2C19 and CYP2D6 alleles across Europe based on data from 82,791 healthy individuals extracted from 79 original publications and, for the first time, provide allele confidence intervals for the general population. We found that frequencies of CYP2D6 gene duplications showed a clear South-East to North-West gradient ranging from <1% in Sweden and Denmark to 6% in Greece and Turkey. In contrast, an inverse distribution was observed for the loss-of-function alleles CYP2D6*4 and CYP2D6*5. Similarly, frequencies of the inactive CYP2C19*2 allele were graded from North-West to South-East Europe. In important contrast to previous work we found that the increased activity allele CYP2C19*17 was most prevalent in Central Europe (25–33%) with lower prevalence in Mediterranean-South Europeans (11–24%). In summary, we provide a detailed European map of common CYP2C19 and CYP2D6 variants and find that frequencies of the most clinically relevant alleles are geographically graded reflective of Europe’s migratory history. These findings emphasize the importance of generating pharmacogenomic data sets with high spatial resolution to improve precision public health across Europe.
Highlights
Interindividual variability in therapeutic drug response can result in adverse drug reactions (ADRs) or lack of efficacy and constitutes a key challenge for health care systems
40–70% of patients experience insufficient drug response or drug toxicity and ADRs account for 6.5% of all hospital admissions of which up to 30% are life threatening in at-risk subpopulations [1,2,3,4]
Interethnic differences in drug pharmacokinetics or dynamics constitute important factors to consider for increasingly multinational drug development programs and genetic variability in drug-metabolizing enzymes constitutes an important factor underlying these differences
Summary
Interindividual variability in therapeutic drug response can result in adverse drug reactions (ADRs) or lack of efficacy and constitutes a key challenge for health care systems. In the present study, we systematically analyzed 79 original publications covering 82,791 healthy volunteers throughout Europe for CYP2C19 and CYP2D6 variants to provide a high-resolution map of pharmacogenetically relevant variability across European populations Analysis of this consolidated data set revealed that the loss-of-function variants CYP2C19*2, CYP2D6*4, and CYP2D6*5 were graded from Northern Europe to the Mediterranean, whereas CYP2D6 duplications showed an inverse pattern. In contrast to previous reports we find clear evidence that CYP2C19*17 is most common in Central Europe, whereas prevalence is lower in South Europeans Combined, these data reveal the extent of intra-European pharmacogenetic variability and underscore the importance of using local genomic information for conducting pharmacogenetic analyzes, clinical trials, and precision public health. For additional information about the haplotypes in question we refer the interested reader to the website of the Pharmacogene Variation Consortium (https://www.pharmvar.org)
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