Marina Jelovac*, Đorđe Pavlović, Biljana Stanković, Nikola Kotur, Vladimir Gašić, Bojan Ristivojević, Sonja Pavlović and Branka Zukić
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
marina.jelovac [at] imgge.bg.ac.rs
Abstract
Many drugs account for an extensive interpatient variability in dose requirement for achieving therapeutic benefit. Said variability is often largely influenced by common genetic variants in several pharmacogenes. Herein we present an overview of pharmacogenomic landscape of Serbian population on the example of 7 actionable pharmacogenes for which Clinical Pharmacogenetics Implementation Consortium issued guidelines for interpretation and use of haplotypes to estimate adequate dose in therapeutics for treatment of cancer, rheumatic and cardiovascular diseases: TPMT, SLCO1B1, NUDT15, UGT1A1, VKORC1, CYP2C9 and CYP4F2.
A cohort of 113 patients from Serbia underwent whole exome sequencing. Generated FASTQ files were aligned to human reference genome build GRCh38 and variants were annotated using in-house pipeline. Calling of star alleles was performed using open-sourced bioinformatics tool Stargazer applied to BAM and VCF files. Subsequent analysis of frequency differences in Serbian versus European population was done using 1000 Genomes Project database and Chi square test in R program.
In 7 analyzed pharmacogenes 23 different haplotypes, denoted as star alleles, were found in total. Nine of these haplotypes had significantly different frequencies in Serbian comparing to European population – CYP4F2*2, variant rs9923231 T in VKORC1, TPMT*20 and TPMT*43, UGT1A1*36 and UGT1A1*80, while in actionable pharmacogene SLCO1B1 three haplotypes (*4, *20 and *37) with significantly higher frequencies in Serbian than in European population were detected.
Presented results show that frequencies of several important pharmacogenomics star alleles differ in Serbian comparing to European population. This could have serious clinical implications and potentially lead to more frequent development of adverse drug reactions when treating patients in need with standard drug doses. In Serbian population a potential for preemptive genotype testing exist when prescribing therapeutics for cancer (TPMT, NUDT15, UGT1A1, SLCO1B1) and rheumatic (SLCO1B1, TPMT) or cardiovascular diseases (VKORC1, CYP2C9, CYP4F2), and population-specific pharmacogenomics aspect should be taken into account for therapy optimization in clinical practice.
Keywords: population pharmacogenomics, bioinformatics, sequencing, biomedicine, precision medicine
Acknowledgement: : This work has been funded by grant from the Ministry of Science, Technological Development and Innovation, Republic of Serbia (Grant No. 451-03-47/2023-01/ 200042) and EC project HORIZON-WIDERA-2021-ACCESS-02-01: PharmGenHUB (GA No. 101059870)