Background Adverse drug reactions are a major concern in drug development and clinical therapy. Genetic polymorphisms in genes involved in drug metabolism and transport are major determinants of treatment efficacy and adverse reactions, and constitute important biomarkers for drug dosing, efficacy and safety. Importantly, human populations and subgroups differ substantially in their pharmacogenetic variability profiles, with important consequences for personalised medicine strategies and precision public health approaches. Despite their long migration history, Ashkenazi Jews constitute a rather isolated population with a unique genetic signature that is distinctly different from other populations.
Objective To provide a comprehensive overview of the pharmacogenetic profile in Ashkenazim.
Methods We analysed next-generation sequencing data from 5076 Ashkenazim individuals and used sequence data from 117 425 non-Jewish individuals as reference.
Results We derived frequencies of 164 alleles in 17 clinically relevant pharmacogenes and derived profiles of putative functional consequences, providing the most comprehensive data set of Jewish pharmacogenetic diversity published to date. Furthermore, we detected 127 variants with an aggregated frequency of 20.7% that were specifically found in Ashkenazim, of which 55 variants were putatively deleterious (aggregated frequency of 9.4%).
Conclusion The revealed pattern of pharmacogenetic variability in Ashkenazi Jews is distinctly different from other populations and is expected to translate into unique functional consequences, especially for the metabolism of CYP2A6, CYP2C9, NAT2 and VKORC1 substrates. We anticipate that the presented data will serve as a powerful resource for the guidance of pharmacogenetic treatment decisions and the optimisation of population-specific genotyping strategies in the Ashkenazi diaspora.
- cyp haplotypes
- personalized medicine
- allele frequency
- genetic variability
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Contributors YZ collected the sequencing data and conducted the data analysis. VML designed and supervised the study. YZ and VML wrote the manuscript. Both authors discussed and agreed on the final version of the manuscript.
Funding This study was supported by the European Union’s Horizon 2020 research and innovation programme U-PGx under grant agreement no 668353 and by the Swedish Research Council (Vetenskapsrådet) (grant numbers 2016-01153 and 2016-01154).
Competing interests VML is a cofounder and owner of HepaPredict AB.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.