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The highest joint prevalence of CYP2C9*2 and VKORC1 variants responsible for warfarin sensitivity in the Croatian Roma compared to 20 populations worldwide

Background: The genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and vitamin K-epoxide reductase complex unit 1 (VKORC1) are major determinants of anticoagulant response to warfarin1. Minor allele carriers of both loci respond in additive manner to a lower dose of warfarin, and they are at risk for adverse drug reaction when usual doses are applied. The Roma (Gypsy) are major European transnational minority population of Indian origin and long- lasting reproductive isolation that could result in specific genetic profile implying that the pharmacogenetic information could not just be extrapolated from surrounding populations. Objective: To investigate the separate and joint minor allele frequencies (MAFs) of the two most important pharmacogenetic loci for warfarin dosage - VKORC1 (rs9923231) and CYP2C9*2 (rs1799853) – in the Roma population and to compare them with 20 populations worldwide. Design: Both loci were genotyped in 422 Roma volunteers living in several regions of Croatia. The comparison is made with 20 populations worldwide (1000 Genomes data extended with the published data for the same countries). Results: Locus rs9923231 has wide geographic variability with extremely high MAF among East Asian populations and almost zero in African populations. However, the rs1799853 MAF distribution does not follow the same global distribution since this allele is not present in East Asian populations, resulting with the highest joint minor alleles frequencies in Roma population amounting 10%. They are followed by European (2.5-7.3%) and South American (0.9- 5.4%), while in South Asian (0.3-1.0%), East Asian (0-0.2) and African (0) populations the risk of combined findings of minor alleles at both loci is negligible or not existent. This finding is primarily result of the highest global MAF for rs1799853 in Croatian Roma (21.6%) in combination with high MAF of rs9923231 in this population (46.1%). Conclusions: Both VKORC1 (rs9923231) and CYP2C9*2 (rs1799853) minor alleles contribute to inter-population difference in adequate warfarin dosage. The present investigation points to the specific Roma population as the one with the highest frequency of combined MAFs at both loci. This puts them at high risk of adverse reaction when warfarin is applied without genetic profiling. Acknowledgements: Croatian Science Foundation grant (HRZZ-IP-2014-09-4454) 1 Fung E et al. Semin Thromb Hemostasis 2012 ; 38:893- 904. ADME ; pharmacogenetics ; VKORC1 ; CYP2C9*2 ; Roma ; 1000 genomes populations ; population genetics ; Croatia Roma ; isolation ; population genetics ; ADME ; pharmacogenetics ; VKORC1 ; CYP3A4 ; NAT2 ; 1000 genomes populations ; Croatia

ADME ; pharmacogenetics ; VKORC1 ; CYP2C9*2 ; Roma ; 1000 genomes populations ; population genetics ; Croatia

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