VKORC1 Research Articles

No evidence of mutations associated with anticoagulant resistance in gene Vkorc1 in brown and black rats from Barcelona

Synanthropic rodents such as the brown rat (Rattus norvegicus) and black rat (Rattus rattus) are a source of disturbance in urban areas and the focus of control programs. Control measures often rely on anticoagulant rodenticides, but their broad use is compromised by the emergence of resistance. Here we studied the prevalence of anticoagulant resistance genotypes in the Vkorc1 gene in rats in the metropolitan area of Barcelona. In this area, part of the management practices to control brown rats include anticoagulant rodenticide use, but rodenticides with different active ingredients are used in rotation. Brown rats were sampled from the sewage system during two periods: from December 2016 to November 2017 when difenacoum and brodifacoum were used, and from August 2021 to July 2022 when bromadiolone was used. Because black rats have just recently been detected in Barcelona, we only studied them during the latter sampling period, with samples obtained from a control action carried out in a green urban area. Exon 3 of the Vkorc1 gene was characterized in both species, while exon 1 was additionally analyzed in black rats. Synonymous mutations, not resulting in amino-acid changes, were found in both exons, indicating no evidence of anticoagulant resistance in the rats of Barcelona. This finding indicates that the current rodent management plan in Barcelona, which involves anticoagulant rotation for brown rats and the use of life capture traps in specific situations for black rats, has helped to prevent the emergence of resistance to anticoagulant rodenticides in rats in Barcelona. Future actions should aim to diversify the control measures included in the rodent management plan.

Vkorc1 polymorphisms of the Norway rats in China: Implications for rodent management and evolutionary origin of anticoagulant resistance mutations

The extensive utilization of second-generation anticoagulant rodenticides (SGARs) has raised concerns regarding non-target animal safety and environmental contamination. It is essential to assess the anticoagulant resistance level in rodent populations and prioritize the use of relative low toxic first-generation anticoagulant rodenticides (FGARs) in susceptible rodent populations. Mutations in the vitamin K epoxide reductase complex subunit 1 (Vkorc1) gene confer anticoagulant resistance in Norway rats. However, the Vkorc1 polymorphisms remain unclear in most Norway rat populations in China although anticoagulant rodenticides have been widely used in China since the 1980s. Analysis of the Vkorc1 polymorphisms in 489 rats across China, combined with in silico binding affinity analysis, revealed three potential resistance mutations A26T, C96Y, and A140T at three distinct locations. In the remaining locations, Vkorc1 resistance mutations were absent, indicating that the FGARs could be effective in these areas. Additional evolutionary analysis of different Vkorc1 mutations suggested that the three missense mutations identified in China might have evolved independently as de novo mutations, and the resistance mutations in Europe are unlikely to be pre-existing variations in China. Further analysis of Vkorc1 haplotypes among European resistant rat populations is essential for understanding the origin of these resistance mutations. These findings emphasize the importance of customizing rodent control strategies in China based on regional resistance levels and gaining insights into the origins of Vkorc1 mutations for more effective rodent management strategies.

Pharmacogenetics of warfarin: A literature review

Warfarin is an oral indirect anticoagulant that is widely used for the prevention of thromboembolic events. Pharmacogenetic testing is the most promising approach to personalizing warfarin treatment. In this review, we aimed to summarize how the patients’ genetic predispositions affect the pharmacokinetics of warfarin, which determines the different dosing regimens for patients. To correctly interpret data in clinical settings, algorithms for selecting the optimal dosing regimen need to be developed that consider the patient’s age, sex, weight, height, health status, and genetic characteristics. These algorithms could help determine the optimal dose, enhance patient adherence to treatment, and increase the physician’s confidence in the treatment safety. Furthermore, although algorithms that consider SNPs in the CYP2C9, VKORC1, and CYP4F2 genes are more effective in predicting warfarin doses, their effectiveness varies according to race.

A survey of VKORC1 missense mutations in eleven Italian islands reveals widespread rodenticide resistance in house mice

To protect native wildlife, more than one hundred rodent eradications have been attempted in the Mediterranean islands by using anticoagulant rodenticides (ARs). Despite their high efficiency, resistance to ARs has been observed in many countries and it is mostly related to missense mutations (SNPs) in the VKORC1 gene. The presence of resistant individuals reduces the efficiency of rodent management, leading to an excessive use of ARs. Thus, the risk of poisoning in non-target species increases. In this study, the first survey of ARs resistance in the house mouse Mus domesticus covering multiple islands in the Mediterranean was performed. Tissue samples of eighty-two mice from eleven islands in Italy were analysed and eight missense SNPs were found. In addition to some well-known missense mutations, such as Tyr139Cys, six new missense SNPs for the house mouse were discovered, four of which were new even for any rodent species. Furthermore, the frequency of Tyr139Cys significantly increased in Ventotene Island after a four-year long rat eradication. This could be due to the selective pressure of ARs that allowed the mice carrying the mutation to survive. This study demonstrates once again the importance of assessing resistance to ARs before undertaking rodent eradications. Indeed, this would allow an informed decision of the most effective AR to use, maximizing the success rate of the eradications and minimizing secondary poisoning and other deleterious effects for non-target species and the environment.

The Influence of Genetic Polymorphisms on Warfarin Dosage Requirements in Cardiac Valve Surgery Patients

Aim: Warfarin, a widely prescribed anticoagulant, exhibits considerable variability in patient response, making its clinical use challenging due to a narrow therapeutic window. This study aimed to evaluate the prevalence of CYP2C9 and VKORC1 gene polymorphisms in a cohort of 87 Turkish patients who underwent cardiac valve surgery and received warfarin therapy, as well as to assess their impact on warfarin dosage requirements. Methods: The frequencies of CYP2C9 and VKORC1 polymorphisms were analyzed, and patients were stratified based on the presence or absence of mutations affecting warfarin dosing. Results: Revealed that patients carrying at least one CYP2C9 or VKORC1 polymorphism required a significantly lower weekly warfarin dose to achieve the optimal international normalized ratio (INR). Conclusion: This study highlights the critical role of genetic factors in determining warfarin dosage and supports the integration of pharmacogenetic testing into clinical practice to personalize warfarin therapy. Such an approach has the potential to enhance treatment outcomes and minimize the risk of adverse events. Further research involving larger sample sizes and diverse patient populations is warranted to validate these findings and refine the current understanding of the genetic determinants of warfarin dosing.

Distribution of anticoagulant resistance in the brown rat in Belgium

Anticoagulant resistance is known as one of the major factors interfering with rodent control. Within this context we investigated the distribution of anticoagulant resistance in Flanders, northern Belgium. From 2003 to 2005, we tested 691 rats from different locations with blood clotting response tests for their susceptibility to the anticoagulant compounds warfarin, bromadiolone and difenacoum. Of these, 119 were also screened for a mutation in the VKORC1 gene that is suspected to be responsible for anticoagulant resistance. Warfarin resistant rats were found in the western and eastern parts of Flanders. The same distribution pattern was found for bromadiolone with the exception of the south-eastern area, where this form of resistance was largely absent. We detected difenacoum resistance in only six rats and did not observe any resistant rats in the central part of Flanders. Susceptible rats were found all over Flanders. Genetic analyses showed that anticoagulant
 resistance in Belgium was related to two different mutations in VKORC1, namely Y139F and L120Q. Our results indicate that rodent control should be regionally tailored to be most effective.

Genetic diversity of variants involved in drug response among Tunisian and Italian populations toward personalized medicine

Adverse drug reactions (ADR) represent a significant contributor to morbidity and mortality, imposing a substantial financial burden. Genetic ancestry plays a crucial role in drug response. The aim of this study is to characterize the genetic variability of selected pharmacogenes involved with ADR in Tunisians and Italians, with a comparative analysis against global populations. A cohort of 135 healthy Tunisians and 737 Italians were genotyped using a SNP array. Variants located in 25 Very Important Pharmacogenes implicated in ADR were extracted from the genotyping data. Distribution analysis of common variants in Tunisian and Italian populations in comparison to 24 publicly available worldwide populations was performed using PLINK and R software. Results from Principle Component and ADMIXTURE analyses showed a high genetic similarity among Mediterranean populations, distinguishing them from Sub-Saharan African and Asian populations. The Fst comparative analysis identified 27 variants exhibiting significant differentiation between the studied populations. Among these variants, four SNPs rs622342, rs3846662, rs7294, rs5215 located in SLC22A1, HMGCR, VKORC1 and KCNJ11 genes respectively, are reported to be associated with ethnic variability in drug responses. In conclusion, correlating the frequencies of genotype risk variants with their associated ADRs would enhance drug outcomes and the implementation of personalized medicine in the studied populations.

Genetic Determinants of Response to Statins in Cardiovascular Diseases.

Despite extensive efforts to identify patients with cardiovascular disease (CVD) who could most benefit from the treatment approach, patients vary in their benefit from therapy and propensity for adverse drug events. Genetic variability in individual responses to drugs (pharmacogenetics) is considered an essential determinant in responding to a drug. Thus, understanding these pharmacogenomic relationships has led to a substantial focus on mechanisms of disease and drug response. In turn, understanding the genomic and molecular bases of variables that might be involved in drug response is the main step in personalized medicine. There is a growing body of data evaluating drug-gene interactions in recent years, some of which have led to FDA recommendations and detection of markers to predict drug responses (e.g., genetic variant in VKORC1 and CYP2C9 genes for prediction of drug response in warfarin treatment). Also, statins are widely prescribed drugs for the prevention of CVD. Atorvastatin, fluvastatin, rosuvastatin, simvastatin, and lovastatin are the most common statins used to manage dyslipidemia. This review provides an overview of the current knowledge on the pharmacogenetics of statins, which are being used to treat cardiovascular diseases.

Exposure and resistance to anticoagulant rodenticides in invasive and endemic Chadian urban rodent species to develop a rational management strategy.

Using a sampling of nearly 300 rodents composed of invasive and endemic rodents collected in six of Chad's largest cities, exposure to ARs was analyzed by their quantification in the liver; the spread of AR resistance alleles was analyzed by Vkorc1 sequencing. We demonstrate the use of both ARs generations in Chadian cities and report the total sequencing of the Vkorc1 for 44 Mastomys natalensis with detection of two different haplotypes, the sequencing of the Vkorc1 for two other endemic rodent species, M. kollmannspergeri and Arvicanthis niloticus, and finally the detection of three new missense mutations - V29E, V69E and D127V - in R. rattus, potentially associated with resistance to ARs. These results should argue for the implementation of a reasoned management of rodent populations in Africa to avoid the spread of ARs resistance alleles. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Association evaluations of oral anticoagulants with dementia risk based on genomic and real-world data

BackgroundSeveral observational studies have suggested that oral anticoagulants (OACs) might reduce the risk of dementia in the elderly, but the evidence is inconclusive. And the consistency of this relationship across different OAC classes and dementia subtypes is still uncertain. MethodsTo comprehensively evaluate this association, we applied Mendelian randomization (MR) combined with pharmacovigilance analysis. MR was used to assess the associations between genetic proxies for three target genes of OACs (VKORC1, F2, and F10) and dementia, including Alzheimer's disease (AD) and vascular dementia (VaD). This genetic analysis was supplemented with real-world pharmacovigilance data, employing disproportionality analysis for more reliable causal inference. ResultsIncreased expression of the VKORC1 gene was strongly associated with increased risk of dementia, especially for AD (OR = 1.28, 95% CI = 1.14–1.43; p value < 0.001). Based on pharmacovigilance data, vitamin K antagonists (VKAs, inhibitors targeting VKORC1) exhibited a protective effect against dementia risk (ROR = 0.43, 95% CI = 0.28–0.67). Additional sensitivity analyses, including different MR models and cohorts, supported these results. Conversely, no strong causal associations of genetically proxied F2 and F10 target genes with dementia and its subtypes were found. ConclusionsThis study reveals that the inhibition of genetically proxied VKORC1 expression or VKAs exposure is associated with a reduced risk of Alzheimer's dementia. However, there is little evidence to support similar associations with direct oral anticoagulants (F2 inhibitors and F10 inhibitors). Further research is warranted to clinically validate our findings.

Widespread distribution of rodenticide resistance-conferring mutations in the Vkorc1 gene among house mouse populations in Portuguese Macaronesian islands and Iberian Atlantic areas

Growing evidence of widespread resistance to anticoagulant rodenticides (ARs) in house mice pose significant challenges to pest control efforts. First-generation ARs were introduced in the early 1950s but resistance to these emerged later that decade. Second-generation rodenticides were then developed, with resistance being reported in the late 1970s. Research has linked resistance to ARs with mutations in the Vkorc1 gene, leading to the use of more toxic and environmentally harmful compounds. In this study, 243 tail tips of house mice from mainland Portugal and Southern Spain, the Azores and Madeira archipelagos were analysed for all 3 exons of the Vkorc1 gene. Mutations L128S, Y139C, along with the so-called spretus genotype Vkorc1spr are considered responsible for reduced susceptibility of house mice to ARs. All these sequence variants were broadly detected throughout the sampling regions. Vkorc1spr was the most often recorded among mainland populations, whereas Y139C was nearly ubiquitous among the insular populations. In contrast, L128S was only detected in mainland Portugal and four islands of the Azores archipelago. All first generation ARs such as warfarin and coumatetralyl are deemed ineffective against all Vkorc1 variants identified in this study. Second-generation bromadiolone and difenacoum should also be discarded to control populations carrying Vkorc1spr, Y139C or L128S mutations. Inadequate use of ARs in regions where resistant animals have been found in large proportions will result in the spreading of rodenticide resistance among rodent populations through the positive selection of non-susceptible individuals. Consequently, ineffectiveness of rodent control will increase and potentiate environmental contamination, hazarding non-target wildlife through secondary poisoning. We highlight the need for Vkorc1 screening as a crucial tool in rodent management, aiding in the selection of the most appropriate control/eradication method in order to prevent misuse of these toxic biocides and the spread of rodenticide resistance among house mouse populations.

An Investigating the Genetic Effect of VKORC1 Gene Polymorphism on Warfarin Response in Egyptian Heart Patients

An Investigating the Genetic Effect of VKORC1 Gene Polymorphism on Warfarin Response in Egyptian Heart Patients

Influence of polymorphisms in CYP2C9, VKORC1, MDR1 and APOE genes on the warfarin maintenance dose in Brazilian patients.

Background: Polymorphisms in the CYP2C9, VKORC1, MDR1 and APOE genes may impact warfarin dose. Aim: To investigate the influence of sociodemographic and clinical factors and polymorphisms *1, *2 and *3 for CYP2C9, -1639G>A for VKORC1, 3435C>T for MDR1, and ϵ2, ϵ3 and ϵ4 for APOE genes on the mean weekly warfarin maintenance dose in adults. Methods: This cross-sectional study recruited a calculated sample of 315 patients in three anticoagulation clinics in Brazil. A model containing the variables significantly associated with warfarin dose was estimated. Results: The mean age of patients was 64.1±13.1 years, with 173 (54.9%) women. Age, use of amiodarone, genotype VKORC1 GA, genotype VKORC1 AA, genotypes CYP2C9*1/*2 or *1/*3 and genotypes CYP2C9*2/*2 or *2/*3 or *3/*3 were associated with a reduced warfarin dose. Conclusion: This study pointed out factors that could impact the management of oral anticoagulation.

#6812 ON THE TOP PHARMACOGENETICS STUDY EXTRACTED FROM EXOME SEQUENCING DONE FOR CHRONIC KIDNEY DISEASES OF UNKNOW ORIGIN

Abstract Background and Aims A recent study from a large cohort published by the Ubiquitous Pharmacogenomic Consortium demonstrates the interest of pre-emptive pharmacogenetic panel testing, with a 30% reduction rate of clinically detectable side-effects. Our laboratory routinely performs diagnostic exome sequencing (ES) for adult patient with kidney disease and more than 2000 patients have been analyzed to date. Patient with chronic kidney diseases (CKD) could benefit from pharmacogenetics information, since they are often polymedicated and efficacy or safety of their medications are known to be influenced by the genetic background. We studied if meaningful pharmacogenetics information could be delivered from exome sequencing data provided for CKD, either retrospectively or prospectively. Method We selected 214 variants of pharmacogenetics relevance, based on evidence and frequency criteria. We evaluated their depth of coverage on 300 patients randomly selected in our CKD cohort. Results Eleven of those 214 variants were not covered by ES. Three of 11 variants were in UGT1A1 and were excluded from analysis since this information is only relevant for Irinotecan treatment. The remaining 8 variants fall in CYP2C19, CYP3A5, CYP3A4, CYP2D6, HLA B (B15:02), HLA A (A31:01), IFNL3, VKORC1 genes: we completed exome data by targeted sanger sequencing for these variants. One challenging region is CYP2D6 given high sequence homology with CYP2D7 and CYP2D8: to assess if we could reliably call variants in this region, we used 7 additional Coriell samples, as 8 others were also assessed with an orthogonal technique. We were able to properly detect variants in these complex regions in all cases, including hybrid genes. Conclusion Our preliminary data show that exome sequencing, initially ordered for CKD, could also be used to deliver pharmacogenetic meaningful information, by adding a few targeted genotyping assays. We currently evaluate the clinical utility and impact of pharmacogenetics in our CKD cohort prospectively.

Allelic Variants in the Warfarin-related Genes VKORC1 and CYP2C9 in a Western Saudi Population

Objectives To investigate the allele and genotype frequencies of the warfarin-related genes VKORC1 (-1639G&gt;A), CYP2C9*2, and CYP2C9*3 among healthy Saudis. Materials and Methods This cross-sectional study involved 125 unrelated healthy Saudis ages 18–60 years visiting the King Abdulaziz University Hospital (KAUH) in Jeddah, Western Saudi Arabia. The Oragene™ DNA saliva collection kits were used to collect and extract DNA from saliva samples. A polymerase chain reaction-restriction fragment length polymorphism analysis was used to detect the mutant alleles. Results Over 51.4% of the Saudi participants carried one or more mutant alleles. The frequency of the VKORC1 (-1639G&gt;A) allele in Saudi was relatively high at 54.8%. The frequencies of the CYP2C9 allele were 19.6% and 54% for the CYP2C9*2 and CYP2C9*3 alleles, respectively, which are substantially more abundant than in other populations. Conclusion The observed high frequencies of VKORC1 (-1639G&gt;A) and CYP2C9*2 and CYP2C9*3 polymorphisms suggest that genetic testing should be considered before initiating warfarin therapy to predict the optimal initial dose of warfarin and minimize warfarin-related side effects.

Vkorc1 gene polymorphisms confer resistance to anticoagulant rodenticide in Turkish rats.

Mutations in Exon 1, 2 and 3 of the vitamin K epoxide reductase complex subunit 1 (Vkorc1) gene are known to lead to anticoagulant rodenticide resistance. In order to investigate their putative resistance in rodenticides, we studied the genetic profile of the Vkorc1 gene in Turkish black rats (Rattus rattus) and brown rats (Rattus norvegicus). In this context, previously recorded Ala21Thr mutation (R. rattus) in Exon 1 region, Ile90Leu mutation (R. rattus, R. norvegicus) in Exon 2 region and Leu120Gln mutation (R. norvegicus) in Exon 3 region were identified as "missense mutations" causing amino acid changes. Ala21Thr mutation was first detected in one specimen of Turkish black rat despite the uncertainty of its relevance to resistance. Ile90Leu mutation accepted as neutral variant was detected in most of black rat specimens. Leu120Gln mutation related to anticoagulant rodenticide resistance was found in only one brown rat specimen. Furthermore, Ser74Asn, Gln77Pro (black rat) and Ser79Pro (brown rat) mutations that cause amino acid changes in the Exon 2 region but unclear whether they cause resistance were identified. In addition, "silent mutations" which do not cause amino acid changes were also defined; these mutations were Arg12Arg mutation in Exon 1 region, His68His, Ser81Ser, Ile82Ile and Leu94Leu mutations in Exon 2 region and Ile107Ile, Thr137Thr, Ala143Ala and Gln152Gln mutations in Exon 3 region. These silent mutations were found in both species except for Ser81Ser which was determined in only brown rats.

The prevalence of pharmacogenetic variants of vitamin K epoxide reductase complex subunit 1 gene (rs9923231), cytochrome P450 family 2 subfamily C member 9 gene (rs1799853) and cytochrome P450 family 3 subfamily-A member-5 gene (rs776746) among 13 ethnic groups of Pakistan.

Pharmacogenomics (PGx) plays a central role in the selection of targeted therapies that underpins precision-medicine. We investigated the prevalence of three important pharmacogenetic variants of VKORC1, CYP2C9, and CYP3A5 genes among Pakistani populations. A total of 1104 individuals were included representing thirteen major ethnicities. Samples were genotyped by using PCR-RFLP analysis. The allelic and genotypic frequencies of the three SNV's were calculated and were compared with the world's population data (ALFA, gnomAD, and 1000Genome, 1K databases), using the chi-square test. We found overall frequencies of functional-alleles of VKORC1 0.43, CYP2C9 0.94, and CYP3A5 0.14 in our population. Data showed a low prevalence of homozygous functional genotypes of VKORC1 (0.18; 0.0-0.45) and CYP3A5 (0.04; 0.0-0.22), and a high frequency of CYP2C9 (0.885; 0.80-1.0) across ethnicities. Genotyping distribution of VKCOR1 functional genotype was varied across ethnic groups such as 0.0-0.10 in Brahuis and Mohanas, Sindhis, Rajputs, and Gujjars populations, 0.11-0.20 in Makranis, Parsis, and Burusho populations, and 0.20-0.30 in Kalash, Kashmiris and Baloch populations. The highest VKORC1 (CC) was found in Pathans (0.45) and Hazaras (0.39) populations. Interestingly, we found a high prevalence of functional genotype CYP2C9 (rs1799853; C) and non-functional genotype of CYP3A5 (rs776746; T) across various ethnic groups of Pakistan. Data regarding prevalence of clinically important pharmacogenomics SNVs could be useful in drug adjustment and avoiding adverse drug reactions in a specific ethnic population. This could help in moving current medical practices toward precision medicine in our part of the world.

The stop-feed effect of cholecalciferol (vitamin D3) and the efficacy of brodifacoum combined with cholecalciferol in Y139C-resistant Norway rats (Rattus norvegicus)

Second-generation anticoagulant rodenticides potentially build persistent residues in animals and accordingly pose a risk of secondary poisoning. We examined the effect of a low concentration of cholecalciferol in brodifacoum bait on bait consumption by Norway rats (Rattus norvegicus Berkenhout 1769) and on the control success in a laboratory study and in field trials. Additionally, the efficacy of both baits was determined against resistant Y139C rats. Cholecalciferol caused a strong stop-feed effect after two days in the laboratory study. On two field study sites each, bait containing either 25 mg kg−1 brodifacoum or 25 mg kg−1 brodifacoum and 100 mg kg−1 cholecalciferol was applied to treat infestations of Norway rats. Infestations were assessed pre- and post-treatment. Rats were radio-tagged, and carcasses were searched for during the treatment period. DNA of each rat was genotyped to determine the resistance status conferred by the VKORC1 gene. On all farms, control success exceeded 90%. On farms treated with brodifacoum only, the ratio of total bait consumption to pre-treatment census was significantly higher (6.6 and 4.8 times) than on farms treated with the combination (2.7 and 2.9 times). 78.8% of 183 rats were confirmed Y139C resistant. Bait ingestion was reduced by almost fifty per-cent when cholecalciferol was added to the bait with no impact on control success. All treatments resulted in control levels exceeding 90%, despite a high proportion of anticoagulant-resistant rats. When the use of highly toxic compounds is required in resistance management, addition of cholecalciferol to these baits may reduce the transfer of residues to the environment.

The role of CYP2C9*2, CYP2C9*3 and VKORC1-1639 variants on the susceptibility of upper gastrointestinal bleeding: A full case-control study.

Purpose: To investigate whether interindividual variability in the CYP2C9 (*2 and *3 alleles) and VKORC1 (rs9923231) genes is associated with increased risk of upper gastrointestinal bleeding (UGIB) in users of non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA). Methods: A full case-control study including 200 cases of patients diagnosed with UGIB and 706 controls was conducted in a Brazilian hospital complex. To perform an analysis of NSAIDs dose-effect, the defined daily dose (DDD) for NSAIDs was calculated in the 7-day etiologic window preceding the data index. Three categories of DDD, considering the genotypes of the genetic variants, were established: non-users of NSAIDs (DDD = 0), DDD ≤0.5, and DDD >0.5. Genetic variants and LDA or NSAIDs use synergism was estimated through Synergism Index (SI) and Relative Excess Risk Due To Interaction (RERI). Results: For DDDs of NSAIDs upward of 0.50, a risk of UGIB was identified in carriers of the *3 allele (OR: 15,650, 95% CI: 1.41-174.10) and in carriers of the variant homozygous genotype (TT) of rs9923231 (OR: 38,850, 95% CI: 2.70-556.00). In LDA users, the risk of UGIB was observed to be similar between carriers of the wild type homozygous genotype and carriers of the variant alleles for the CYP2C9 and VKORC1 genes. No synergism was identified. Conclusion: Our findings suggest an increased risk of UGIB in carriers of the variant allele of rs9923231 and in carriers of the *3 allele associated with doses of NSAIDs greater than 0.5. Hence, the assessment of these variants might reduce the incidence of NSAIDs-related UGIB and contribute to the safety of the NSAIDs user.

Warfarin hypersensitivity in the internist's practice: a case report

Anticoagulants are widely used in clinical practice to reduce the risk of cardiovascular events. However, there are associated clinical conditions that require coagulation system monitoring due to an increased risk of bleeding. In clinical practice, cases of warfarin hypersensitivity due to gene polymorphisms are known. Taking warfarin in such a situation is often manifested by massive bleeding that threatens the patient's life. Sixty seven-years-old female patient was admitted to the internal medicine department of Rostov State Medical University clinic in March 2022. The day before, she noted severe abdominal pain, loose bloody stool. An outpatient examination revealed an increase in international normalized ratio to 9,42, thrombin time &gt;30 sec. There were no signs of primary gastrointestinal pathology. According to anamnesis, on January 21, 2022, the patient underwent mechanical aortic valve replacement, in connection with which warfarin was prescribed at a dose of 2,5 mg/day. After establishing hypocoagulation, warfarin was discontinued. A pharmacogenetic analysis was performed, which established the carriage of polymorphisms of cytochrome P450 system genes, the homozygous mutation 1075A&gt;C (CYP2C9 (*3/*3)), and the heterozygous mutation of the vitamin K reductase gene VKORC1 G(-1639)A (VKORC1 GA). The individual dosage of warfarin was calculated according to International Warfarin Pharmacogenetics Consortium guidelines, which was 9 mg/week. After adjusting the dose of warfarin, the level of international normalized ratio decreased to 3,61, thrombin time to 13 sec. The patient was discharged with recommendations to follow an individual warfarin regimen and monitor coagulation parameters. The presence of hypersensitivity to warfarin is not a reason for its complete withdrawal in situations requiring longterm anticoagulation. In this regard, it is necessary for the doctor to be vigilant when prescribing warfarin to a patient, understanding the causes and methods for diagnosing hypersensitivity to warfarin, and timely correction of its dosage.