Background: Genetic variability in some of the genes that affect absorption, distribution, metabolism, and elimination ("pharmacogenes") can significantly influence an individual's response to the drug and consequently the effectiveness of treatment and possible adverse drug events. The rapid development of sequencing methods in recent years and consequently the increased integration of next-generation sequencing technologies into the clinical settings has enabled extensive genotyping of pharmacogenes for personalized treatment. The aim of the present study was to investigate the frequency and variety of potentially actionable pharmacogenetic findings in the Slovenian population. Methods: De-identified data from diagnostic exome sequencing in 1904 cases submitted to our institution were analyzed for variants within 293 genes associated with drug response. Filtered variants were classified according to population frequency, variant type, the functional impact of the variant, pathogenicity predictions and characterization in the Pharmacogenomics Knowledgebase (PharmGKB) and ClinVar. Results: We observed a total of 24 known actionable pharmacogenetic variants (PharmGKB 1A or 1B level of evidence), comprising approximately 26 drugs, of which, 12 were rare, with the population frequency below 1%. Furthermore, we identified an additional 61 variants with PharmGKB 2A or 2B clinical annotations. We detected 308 novel/rare potentially actionable variants: 177 protein-truncating variants and 131 missense variants predicted to be pathogenic based on several pathogenicity predictions. Conclusion: In the present study, we estimated the burden of pharmacogenetic variants in nationally based exome sequencing data and investigated the potential clinical usefulness of detected findings for personalized treatment. We provide the first comprehensive overview of known pharmacogenetic variants in the Slovenian population, as well as reveal a great proportion of novel/rare variants with a potential to influence drug response.
Keywords: PharmGKB; Slovenian population; next-generation sequencing; personalized medicine; pharmacogenomics.