Despite the widespread use of anticoagulant rodenticides in baits for controlling commensal rodent pests, their application is problematic due to secondary intoxication and increasing resistance. In contrast to studies on Western European house mice (Mus musculus domesticus), few resistance studies have focused on Eastern European house mice (M. musculus musculus), which have a western distribution boundary in the Czech Republic. This study newly analysed the VKORC1 gene in M. m. musculus field populations from Czech farms and grain stores and identified a nonsynonymous mutation Tyr139Phe. This mutation was common throughout the Czech Republic and was present in 80.2% of the 86 individuals sampled. Additionally, all individuals exhibited a genotype with three synonymous mutations specific to the subspecies M. m. musculus. The functional (mortality-survival) response of the Tyr139Phe mutation was validated in a laboratory choice feeding test using bromadiolone-based bait, where all resistant homozygous individuals survived, while all susceptible mice died, with a mean survival of 6.9 days.

• Klíčová slova
• Mus musculus musculus, VKORC1, Anticoagulant rodenticides, Resistance, Rodent pests,
• MeSH
• 4-hydroxykumariny MeSH
• antikoagulancia * farmakologie   MeSH
• epoxidreduktasy vitaminu K * genetika   MeSH
• genotyp MeSH
• léková rezistence genetika   MeSH
• mutace * MeSH
• myši MeSH
• rodenticidy * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• 4-hydroxykumariny MeSH
• antikoagulancia * MeSH
• bromadiolone MeSH Prohlížeč
• epoxidreduktasy vitaminu K * MeSH
• rodenticidy * MeSH

The genetic basis of variability in drug response is at the core of pharmacogenomics (PGx) studies, aiming at reducing adverse drug reaction (ADR), which have interethnic variability. This study used the Kardiovize Brno 2030 random urban Czech sample population to analyze polymorphisms in a wide spectrum of genes coding for liver enzymes involved in drug metabolism. We aimed at correlating real life drug consumption with pharmacogenomic profile, and at comparing these data with the SUPER-Finland Finnish PGx database. A total of 250 individuals representative of the Kardiovize Brno 2030 cohort were included in an observational study. Blood DNA was extracted and 59 single nucleotide polymorphisms within 13 genes (BCHE, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A5, F2, F5, IFNL3, SLCO1B1, TPMT, UGT1A1, VKORC1), associated to different drug metabolizing rates, were characterized by genotyping using a genome wide commercial array. Widely used drugs such as anti-coagulant warfarin and lipid lowering agent atorvastatin were associated to an alarmingly high percentage of users with intermediate/poor metabolism for them. Significant differences in the frequency of normal/intermediate/poor/ultrarapid/rapid metabolizers were observed for CYPD26 (p<0.001), CYP2C19 (p<0.001) and UGT1A1 (p<0.001) between the Czech and the Finnish study populations. Our study demonstrated that administration of some popular drugs to a Czech random sample population is associated with different drug metabolizing rates and therefore exposing to risk for ADRs. We also highlight interethnic differentiation of some common pharmacogenetics variants between Central (Czech) and North European (Finnish) population studies, suggesting the utility of PGx-informed prescription based on variant genotyping.

• MeSH
• cytochrom P-450 CYP2D6 genetika   MeSH
• cytochrom P450 CYP2C19 genetika   metabolismus   MeSH
• cytochrom P450 CYP2C9 genetika   metabolismus   MeSH
• epoxidreduktasy vitaminu K genetika   MeSH
• farmakogenetika * MeSH
• genotyp MeSH
• lidé MeSH
• polymorfismus genetický * MeSH
• polypeptid C přenášející organické anionty genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• cytochrom P-450 CYP2D6 MeSH
• cytochrom P450 CYP2C19 MeSH
• cytochrom P450 CYP2C9 MeSH
• epoxidreduktasy vitaminu K MeSH
• polypeptid C přenášející organické anionty MeSH
• SLCO1B1 protein, human MeSH Prohlížeč
• VKORC1 protein, human MeSH Prohlížeč

Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes. Our data show significant inter-population pharmacogenomic biomarker allele frequency differences, particularly in 7 clinically actionable pharmacogenomic biomarkers in 7 European populations, affecting drug efficacy and/or toxicity of 51 medication treatment modalities. These data also reflect on the differences observed in the prevalence of high-risk genotypes in these populations, as far as common markers in the CYP2C9, CYP2C19, CYP3A5, VKORC1, SLCO1B1 and TPMT pharmacogenes are concerned. Also, our data demonstrate notable differences in predicted genotype-based warfarin dosing among these populations. Our findings can be exploited not only to develop guidelines for medical prioritization, but most importantly to facilitate integration of pharmacogenomics and to support pre-emptive pharmacogenomic testing. This may subsequently contribute towards significant cost-savings in the overall healthcare expenditure in the participating countries, where pharmacogenomics implementation proves to be cost-effective.

• MeSH
• antikoagulancia aplikace a dávkování   farmakokinetika   MeSH
• cytochrom P450 CYP2C9 genetika   MeSH
• epoxidreduktasy vitaminu K genetika   MeSH
• etnicita genetika   MeSH
• farmakogenetika * MeSH
• genetické markery * MeSH
• lidé MeSH
• shluková analýza MeSH
• warfarin aplikace a dávkování   farmakokinetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• antikoagulancia MeSH
• cytochrom P450 CYP2C9 MeSH
• epoxidreduktasy vitaminu K MeSH
• genetické markery * MeSH
• VKORC1 protein, human MeSH Prohlížeč
• warfarin MeSH

Resistance of rodents to anticoagulant rodenticides has emerged in several areas across the world. Single nucleotide mutations in the vkorc1 gene have been shown to elicit various levels of anticoagulant resistance, and these mutations are prevalent in several Rattus and Mus musculus populations. In sub-Saharan Africa, the Natal multimammate mouse, Mastomys natalensis, is one of the most damaging pests to crops, and anticoagulant poisons such as bromadiolone are frequently used to control these rodents in agricultural fields. Here, we investigate if vkorc1 shows any polymorphism in natural populations of M. natalensis. We sequenced the third exon of vkorc1 of 162 M. natalensis captured from 14 different agricultural sites in Morogoro Region, Tanzania. In addition to 6 SNPs in the noncoding flanking region, we detected 3 nonsynonymous SNPs in this exon: 10 animals (6.2%) carried a Leu108Val variant, 2 animals (1.2%) an Ala140Thr variant, and 1 animal (0.6 %) an Arg100His variant, all 3 in heterozygous form. Ala140Thr is just one residue from a mutation known to be involved in anticoagulant resistance in Rattus and Mus. While in vitro or in vivo experiments are needed to link vkorc1 genetic polymorphisms to level of VKOR activity and anticoagulant susceptibility, our results suggest that M. natalensis individuals may vary in their response to anticoagulant rodenticides. This is the first vkorc1 sequence data from a species outside the Rattus or Mus genera, and for the first time from a rodent species endemic to Africa.

• Klíčová slova
• anticoagulants, bromadiolone, poison resistance, polymorphism, rodent.,
• MeSH
• antikoagulancia MeSH
• epoxidreduktasy vitaminu K genetika   MeSH
• exony MeSH
• frekvence genu MeSH
• genotyp MeSH
• haplotypy MeSH
• jednonukleotidový polymorfismus * MeSH
• membránové proteiny genetika   MeSH
• mitochondriální DNA genetika   MeSH
• modely genetické MeSH
• Murinae genetika   MeSH
• rodenticidy MeSH
• sekvenční analýza DNA MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Tanzanie MeSH
• Názvy látek
• antikoagulancia MeSH
• epoxidreduktasy vitaminu K MeSH
• membránové proteiny MeSH
• mitochondriální DNA MeSH
• rodenticidy MeSH

BACKGROUND: Warfarin is commonly used for the treatment and prevention of arterial and venous thromboembolism but its use is hindered by the risk of bleeding. The main reason for this risk is a narrow therapeutic index and a wide response variability after warfarin treatment. These shortcomings affect clinical outcomes including bleeding complications and may be associated with variant polymorphisms in the CYP2C9 and VKORC1 genes. AIM: It was the aim of this study to assess the impact of the total variant allele count of CYP2C9 and VKORC1 genes on bleeding related to warfarin treatment. METHODS: In a retrospective cohort-design study, patients were genotyped for polymorphisms in genes CYP2C9 (*1, *2, *3) and VKORC1 (haplotype A, B). Extensive clinical data were obtained. Adjusted hazard ratios (HR) for the occurrence of major bleeding events (MBE) were counted separately for the induction and maintenance phases of warfarin therapy. RESULTS: Out of the 329 patients in our clinical database, 194 patients were eligible and included in the analysis. MBE occurred in 51 patients (26.3%) during a mean follow-up of 26 months: 6 patients (11.8%) experienced early MBE during warfarin initiation, and 45 MBE occurred during the maintenance phase. The adjusted HR for MBE risk for patients with any CYP2C9 variant allele was 1.962 [95% confidence interval (CI) 1.08-3.56, p = 0.027]; for the VKORC1 AA haplotype, HR was 1.841 (95% CI 0.97-3.48, p = 0.06), while for 3 variant allele carriers of both genes, HR was 4.34 (95% CI 1.95-9.65, p < 0.001). Despite the insignificant association of the VKORC1 genotype with bleeding in our study, we have noted a warfarin dose-dependent effect with risk significance ascending: CYP2C9 *1/*1 + VKORC1 B/B < CYP2C9 *1/*1 + VKORC1 A/B < CYP2C9 *1/*2 + VKORC1 B/B. CONCLUSION: Patients who are carriers of 3 variant alleles of the genes CYP2C9 and VKORC1 exhibited a significantly higher risk of MBE during the initiation and maintenance phases of warfarin therapy. Vigilant and careful management of patients with a higher variant allele count, including switching to newer anticoagulants, could be considered in this high-risk cohort.

• MeSH
• alely MeSH
• antikoagulancia škodlivé účinky   MeSH
• aromatické hydroxylasy genetika   MeSH
• cytochrom P450 CYP2C9 MeSH
• epoxidreduktasy vitaminu K genetika   MeSH
• genetická variace MeSH
• krvácení chemicky indukované   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• warfarin škodlivé účinky   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antikoagulancia MeSH
• aromatické hydroxylasy MeSH
• CYP2C9 protein, human MeSH Prohlížeč
• cytochrom P450 CYP2C9 MeSH
• epoxidreduktasy vitaminu K MeSH
• VKORC1 protein, human MeSH Prohlížeč
• warfarin MeSH