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Vitamin K–dependent coagulation factors deficiency (VKCFD) is a rare autosomal recessive genetic disease characterized by impaired levels of multiple coagulation factors (II, VII, IX, and X) and natural anticoagulants (proteins C and S). VKCFD is part of familial multiple coagulation factor deficiencies, reporting overall 50 affected families thus far. Disease manifestations are quite heterogeneous, bleeding symptoms may vary, and even, although generally mild, some patients may succumb to fatal outcomes. VKCFD diagnosis may be delayed because the disease phenotype simulates the most frequently acquired deficiencies of vitamin K. First-line coagulation assays, prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT), are both prolonged; mixing test typically normalizes the clotting times; and vitamin K–dependent coagulation factors will be variably decreased. Molecularly, VKCFD is associated with mutations in γ-glutamyl-carboxylase (GGCX) or vitamin K epoxide reductase complex subunit 1 (VKORC1) genes. Vitamin K is involved not only in the biosynthesis of coagulation proteins but also in bone metabolism and cell proliferation. Therapeutic options are based on vitamin K supplementation, coagulation factors (prothrombin complex), and fresh frozen plasma, in case of severe bleeding episodes. Two case studies here illustrate the diagnostic challenges of VKCFD: case 1 depicts a woman with a history of bleeding episodes, diagnosed, only in her third decade of life with inherited homozygous GGCX gene mutation. Case 2 shows a man with an acquired vitamin K deficiency caused by Crohn's disease. Better understanding of GGCX and VKORC1 mutations aids in prognosis and treatment planning, with emerging insights suggesting potential limitations in the effectiveness of vitamin K supplementation in certain mutations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The widespread use of anticoagulant rodenticide for controlling commensal rodent pests over the past 50 years has raised concerns about the development of genetic resistance that could diminish the efficacy of these toxicants. These rodenticides primarily target the VKORC1 protein synthesized by the Vkorc1 gene. Mutations in the 139 codon altering binding sites and conferring resistance. While studies in Europe and Asia have documented such Vkorc1 mutations and associated anticoagulant rodenticide resistance in commensal rodents, few investigations have explored this issue in the Americas according to the Rodenticide Resistance Action Committee (RRAC). This study is one of the first efforts to survey Vkorc1 resistance mutations in commensal rodents in eastern North America. The lack of genetic mutations in sampled Norway rats collected from Richmond, Virginia and Helsinki Finland provides a baseline for future monitoring as anticoagulant rodenticide selection pressure continues. However, as Norway rat populations continue to grow, regular screening will be critical for early detection of rodenticide resistant genotypes. Municipalities should incorporate Vkorc1 resistance testing into integrated pest management (IPM) programs for rodents. If resistance alleles emerge, control strategies may need to transition towards alternative toxicant modes of control and greater emphasis on IPM tactics that reduce food and harborage resources for these rodents.

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.

Rodent management involves the use of anticoagulant rodenticides (ARs). This use has resulted in the selection of numerous resistance alleles in the Vkorc1 gene, encoding the target enzyme of ARs. In Africa, although rodents are a major problem as a consequence of their transport and transmission of zoonotic pathogens, and damage to crops, the use of ARs and the spread of resistance alleles are poorly documented. We attempted to address both issues in Chad which is one of the largest countries in Africa. Owing to its location at the crossroads of central and northern Africa, Chad is representative of many African countries. Methods: 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. Results: 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. Discussion: 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. [ABSTRACT FROM AUTHOR]

Objective: Warfarin is a widely prescribed narrow therapeutic index anticoagulant. Determining proper warfarin dosage remains problematic due to its narrow therapeutic index and genetic variations from individual to individual. The administration of incorrect doses of warfarin can catastrophic adverse events. Observational studies have demonstrated single nucleotide polymorphisms in CYP2C9 and VK0RC1 significantly affect warfarin dose requirements. The present study aimed to examine the influences of various genotypes on warfarin dose requirements among Iranian patients. Methods: Blood samples were taken from 117 patients and stored in tubes containing EDTA. DNA extraction was performed on the blood samples and the different alleles and genotypes of the studied SNPs were identified and recorded by the PCR-RFLP technique. Results: Of the 117 patients, no significant differences in the mean daily warfarin dose requirement were found among the genotypes of polymorphism CYP2C9 * 3 (1075A> C). However, there were significant differences among the genotypes of CYP2C9 * 2 (430C> T). The mean daily warfarin dose requirements were significantly different among wild genotypes, heterozygotes and mutants in the two polymorphisms of VKORC1 (1173C> T) and VKORC1(1639G> A). Conclusion: The results of our study demonstrated that CYP2C9 and VKORC1 polymorphisms have significant effect on warfarin maintenance dose requirements in iranian patients which would help improve the prediction of warfarin dose requirements and minimize the chance of over-anticoagulation or under-anticoagulation. [ABSTRACT FROM AUTHOR]

Objective: Pharmacogenomics plays an important role in drug metabolism. A stable anticoagulation is important for primary and secondary prevention of cardioembolic stroke and cerebral venous sinus thrombosis (CVST). We report the role of cytochrome P450 (CYP2C9*2/*3) and vitamin K epoxide reductase subunit 1 (VKORC1) genotypes and acquired causes in maintaining stability of anticoagulation following acenocoumarin in cardioembolic stroke and CVST. Methods: The study comprised 157 individuals with cardioembolic stroke and CVST who were on acenocoumarin. Their comorbidities, comedication, and dietary habits were noted. Prothrombin time and international normalized ratio (INR) were measured during follow-up, and the coagulation status was categorized as stable (>50% occasions in therapeutic range) and unstable (>50% below and above therapeutic range). Genotyping of VKORC1, CYP2C9*2, and CYP2C9*3 was done by polymerase chain reaction-restriction fragment length polymorphism. Bleeding and embolic complications were noted. The predictors of unstable INR were evaluated using multivariate analysis. Results: INR was stable in 47.8% and unstable in 52.2% of patients. Patients with mutant genotypes required low dose of acenocoumarin. The predictors of unstable INR were metallic valve (odds ratio [OR] 4.07, 95% confidence interval [CI] 1.23–13.49, P = 0.02), use of digoxin (OR 0.031, 95% CI 0.13–0.74, P = 0.09), proton pump inhibitor (OR 0.23, 95% CI 0.06–0.91, P = 0.037), sodium valproate (OR 0.22, 95% CI 0.05–0.85, P = 0.029), and CYP2C9*2 genotype (OR 5.57, 95% CI 1.19–26.06, P = 0.02). Conclusions: Variant genotypes of VKORC1, CYP2C9*2, and CYP2C9*3 required lower dose of acenocoumarin, and CYP2C9*2 was associated with unstable INR. Comedication is a modifiable risk factor that needs attention.

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). Conclusions: 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. [ABSTRACT FROM AUTHOR]

Pharmacogenomics is the examination of how genetic variation influences drug metabolism and response, in terms of both efficacy and safety. In cardiovascular disease, patient‐specific diplotypes determine phenotypes, thereby influencing the efficacy and safety of drug treatments, including statins, antiarrhythmics, anticoagulants and antiplatelets. Notably, polymorphisms in key genes, such as CYP2C9, CYP2C19, VKORC1 and SLCO1B1, significantly impact the outcomes of treatment with clopidogrel, warfarin and simvastatin. Furthermore, the CYP2C19 polymorphism influences the pharmacokinetics and safety of the novel hypertrophic cardiomyopathy inhibitor, mavacamten. In this review, we critically assess the clinical application of pharmacogenomics in cardiovascular disease and delineate present and future utilization of pharmacogenomics. This includes insights into identifying missing heritability, the integration of whole genome sequencing and the application of polygenic risk scores to enhance the precision of personalized drug therapy. Our discussion encompasses health economic analyses that underscore the cost benefits associated with pre‐emptive genotyping for warfarin and clopidogrel treatments, albeit acknowledging the need for further research in this area. In summary, we contend that cardiovascular pharmacogenomic analyses are underpinned by a wealth of evidence, and implementation is already occurring for some of these gene–drug pairs, but as with any area of medicine, we need to continually gather more information to optimize the use of pharmacogenomics in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: Pharmacogenomics plays an important role in drug metabolism. A stable anticoagulation is important for primary and secondary prevention of cardioembolic stroke and cerebral venous sinus thrombosis (CVST). We report the role of cytochrome P450 (CYP2C9*2/*3) and vitamin K epoxide reductase subunit 1 (VKORC1) genotypes and acquired causes in maintaining stability of anticoagulation following acenocoumarin in cardioembolic stroke and CVST. Methods: The study comprised 157 individuals with cardioembolic stroke and CVST who were on acenocoumarin. Their comorbidities, comedication, and dietary habits were noted. Prothrombin time and international normalized ratio (INR) were measured during follow-up, and the coagulation status was categorized as stable (>50% occasions in therapeutic range) and unstable (>50% below and above therapeutic range). Genotyping of VKORC1, CYP2C9*2, and CYP2C9*3 was done by polymerase chain reaction-restriction fragment length polymorphism. Bleeding and embolic complications were noted. The predictors of unstable INR were evaluated using multivariate analysis. Results: INR was stable in 47.8% and unstable in 52.2% of patients. Patients with mutant genotypes required low dose of acenocoumarin. The predictors of unstable INR were metallic valve (odds ratio [OR] 4.07, 95% confidence interval [CI] 1.23-13.49, P = 0.02), use of digoxin (OR 0.031, 95% CI 0.13-0.74, P = 0.09), proton pump inhibitor (OR 0.23, 95% CI 0.06-0.91, P = 0.037), sodium valproate (OR 0.22, 95% CI 0.05-0.85, P = 0.029), and CYP2C9*2 genotype (OR 5.57, 95% CI 1.19-26.06, P = 0.02). Conclusions: Variant genotypes of VKORC1, CYP2C9*2, and CYP2C9*3 required lower dose of acenocoumarin, and CYP2C9*2 was associated with unstable INR. Comedication is a modifiable risk factor that needs attention. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a systemic inflammatory disorder characterized by granuloma formation in various organs. It has been associated with nephrolithiasis. The vitamin K epoxide reductase complex subunit 1 (VKORC1) gene, which plays a crucial role in vitamin K metabolism, has been implicated in the activation of proteins associated with calcification, including in the forming of nephrolithiasis. This study aimed to investigate the VKORC1 C1173T polymorphism (rs9934438) in a Dutch sarcoidosis cohort, comparing individuals with and without a history of nephrolithiasis. Retrospectively, 424 patients with sarcoidosis were divided into three groups: those with a history of nephrolithiasis (Group I: n = 23), those with hypercalcemia without nephrolithiasis (Group II: n = 38), and those without nephrolithiasis or hypercalcemia (Group III: n = 363). Of the 424 sarcoidosis patients studied, 5.4% had a history of nephrolithiasis (Group I), only two of whom possessed no VKORC1 polymorphisms (OR = 7.73; 95% CI 1.79–33.4; p = 0.001). The presence of a VKORC1 C1173T variant allele was found to be a substantial risk factor for the development of nephrolithiasis in sarcoidosis patients. This study provides novel insights into the genetic basis of nephrolithiasis in sarcoidosis patients, identifying VKORC1 C1173T as a potential contributor. Further research is warranted to elucidate the precise mechanisms and explore potential therapeutic interventions based on these genetic findings. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to investigate the association between VKORC1 and CYP2C9 genes polymorphisms and the maintenance dose of warfarin in Peruvian patients. Methods: An observational study was conducted on outpatients from the Hospital Grau ESSALUD in Lima, Peru. The participants were selected using nonprobabilistic convenience sampling. Inclusion criteria required patients to have been on anticoagulation therapy for >3 months, maintain stable doses of warfarin (consistent dose for at least 3 outpatient visits), and maintain an international normalized ratio within the therapeutic range of 2.5–3.5. DNA samples were obtained from peripheral blood for gene analysis. Results: Seventy patients (mean age of 69.6 ± 13.4 years, 45.7% female) were included in the study. The average weekly warfarin dose was 31.6 ± 15.2 mg. The genotypic frequencies of VKORC1 were as follows: 7.1% (95% confidence interval, 2.4–15.9) for AA; 44.3% (32.4–56.7) for GA; and 48.6% (36.4–60.8) for GG. No deviation from the Hardy–Weinberg equilibrium was observed in the variants studied (P =.56). The mean weekly warfarin doses for AA, GA and GG genotypes were 16.5 ± 2.9, 26.5 ± 9.5 and 37.9 ± 17.1 mg, respectively (P <.001). The genotypic frequencies of CYP2C9 were as follows: 82.8% (72.0–90.8) for CC (*1/*1); 4.3% (1.0–12.0) for CT (*1/*2); and 12.9% (6.1–23.0) for TT (*2/*2). We did not find a significant association between the CYP2C9 gene polymorphism and the dose of warfarin. Conclusions: The AA genotype of the VKORC1 gene was associated with a lower maintenance dose of warfarin in Peruvian patients. [ABSTRACT FROM AUTHOR]

Li Zhao,1 Zhenguo Zhai,2 Pengmei Li1 1Pharmacy Department, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of ChinaCorrespondence: Pengmei Li, Pharmacy Department, China-Japan Friendship Hospital, No. 2 Yinghua East Road, Beijing, People’s Republic of China, Tel +86-1084205661, Email lipengmei@yeah.netAbstract: One 59-year-old female patient with deep venous thrombosis (DVT) and pulmonary embolism (PE) was treated with 6 mg warfarin once daily as an anticoagulant. Before taking warfarin, her international normalized ratio (INR) was 0.98. Two days after warfarin treatment, her INR did not change from baseline. Due to the high severity of the PE, the patient needed to reach her target range (INR goal = 2.5, range = 2~3) rapidly, so the dose of warfarin was increased from 6 mg daily to 27 mg daily. However, the patient’s INR did not improve with the dose escalation, still maintaining an INR of 0.97– 0.98. We drew a blood sample half an hour before administering 27 mg warfarin and detected single nucleotide polymorphism for the following genes, which were identified to be relevant with warfarin resistance: CYP2C9 rs1799853, rs1057910, VKORC1 rs9923231, rs61742245, rs7200749, rs55894764, CYP4F2 rs2108622, and GGCX rs2592551. The trough plasma concentration of warfarin was 196.2 ng/mL after 2 days of warfarin administration with 27 mg QD, which was much lower than the therapeutic drug concentration ranges of warfarin (500– 3,000 ng/mL). The genotype results demonstrate that the CYP4F2gene has rs2108622 mutation which can explain some aspect of warfarin resistance. Further investigations are necessary to fully characterize other pharmacogenomics or pharmacodynamics determinants of warfarin dose-response in Chinese.Keywords: anticoagulation, warfarin resistance, CYP2C9, VKORC1, CYP4F2, GGCX, warfarin plasma concentration

Background/Aim: Warfarin is one of the most common orally prescribed anticoagulant in patients with deep venous thrombosis, myocardial or cerebral infarctions. The main side effects of non-adequate dose of these drugs are prolonged peripheral or internal bleeding. VKORC1 1173C>T polymorphism (rs9934438) is of particular importance, since carriers of non-wild type allele correlates with the lower dosage of warfarin therapy. Thus, the aim of the research was to determine the distribution of 1173C>T polymorphism in population of the Republic of Srpska, Bosnia and Herzegovina (RS) and to compare results with frequencies in other populations. Methods: A total of 124 healthy participants of both genders were enrolled in the study, from all parts of the RS. Molecular genotyping was performed by real-time PCR, using drug metabolism assays according to the manufacturer's instructions. Results: Of the total number, 22 subjects (17.74 %) were genotyped as CC, 69 subjects (55.65 %) as CT and 33 subjects (26.61 %) as TT. The frequencies of alleles C and T were 45.18 % and 54.82 %, respectively. No statistical significance was found among allele distribution between genders (ch² = 0.236; p = 0.627). All observed genotype frequencies were in Hardy-Weinberg equilibrium. No statistical significance was observed among the frequency of minor T allele between presented findings and other European countries, besides Russia (p = 0.021). Conclusion: This was the first study analysing the distribution of rs9934438 alleles in population of the RS. These findings will be helpful in better and more precise drug prescribing in patients who require anticoagulant therapy.

Objectives The fact that a lower warfarin maintenance dose is required by Asian populations is well-known. Currently, the American College of Chest Physicians recommends commencing warfarin at a dose between 5 and 10 mg for venous thromboembolism (VTE). However, the optimal initiating dose in Asians is unknown. This study aimed to evaluate the efficacy of a 3 mg versus a 5 mg of warfarin initiating dose and a corresponding nomogram in patients with VTE. Methods Eligible patients were randomized to receive 3 mg or 5 mg per day warfarin for the first 2 days of treatment. The subsequent dose was adjusted according to the warfarin nomogram. The primary outcome was the number of patients who achieved an INR 2.0–3.0 within 8 days. Results Fifty-six patients were enrolled. There was no significant difference in baseline characteristics between the groups. Seventeen (60.7%) patients in the 3-mg group and 22 (78.6%) patients in the 5-mg group achieved a therapeutic INR within 8 days (p = 0.146). However, there were significantly more patients in the 5-mg group who achieved the target INR on day 5 (53.6% vs 25.0%, p = 0.029). Furthermore, VKORC1-1639G > A was associated with an increased likelihood to achieve the target INR within 5 days (OR 3.81, 95%CI 1.19–12.16, p = 0.021). Conclusions The efficacy of a 3 mg warfarin starting dose with subsequent dose adjustment was similar to that of 5 mg on day 8 after warfarin initiation. However, a 5 mg initiating dose resulted in more patients who achieved therapeutic INR on day 5.

Abstract Background Warfarin is the most widely used oral anticoagulant; nevertheless, dosing of warfarin is problematic for clinicians worldwide. Inter-individual variability in response to warfarin is attributed to genetic as well as non-genetic factors. Pharmacogenomics studies have identified variants in CYP2C9 and VKORC1 genes as significant predictors of warfarin dose, however, phenotypes of rare variants are not well characterized. Case presentation We report a case of hyper-responsiveness to warfarin in a 22-year-old outpatient with Crohn's disease who presented with a swollen, red, and painful left calf. Deep venous thrombosis (DVT) in the left lower extremity was confirmed via ultrasonography, and hence, anticoagulation therapy of heparin and concomitant warfarin was initiated. Warfarin dose of 7.5 mg/day was estimated by the physician based on clinical factors. Higher than the expected international normalized ratio (INR) value of 4.5 necessitated the reduction of the warfarin dose to 5 and eventually to 2.5 mg/day to reach a therapeutic INR value of 2.6. Pharmacogenetic profiling of the VKORC1 -1639G > A and CYP2C9 *2, *3, *4, *5, *8, *14, *20, *24, *26, *33, *40, *41, *42, *43, *45, *46, *55, *62, *63, *66, *68, *72, *73 and *78 revealed a VKORC1-1639GA/CYP2C9*1*46 genotype. The lower catalytic activity of the CYP2C9*46 (A149T) variant was previously reported in in vitro settings. Conclusions This is the first report on a case of warfarin hyper-responsive phenotype of a patient with the heterozygous CYP2C9*1*46 polymorphism.

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 norvegiens). 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. [ABSTRACT FROM AUTHOR]

The aim. To evaluate the efficacy and safety of warfarin (WF) therapy in patients with atrial fibrillation (AF) using pharmacogenetic dosing method at an anticoagulant monitoring office according to the results of a one-year prospective follow-up. Materials and methods. The study involved 110 patients with AF (mean age 68.72 ± 0.79; men – 57, women – 53). By the method of stratified randomization, the patients with AF were divided into two groups: the main group – 50 patients with AF and genotype-guided dosing method, the control group – 60 patients with AF and clinical dosing method. The outcomes were examined after the one-year follow-up: excessive hypocoagulation episodes (INR > 4) and bleeding. CYP2C9, CYP4F2, VKORC1 gene polymorphisms were determined using multiplex real time polymerase chain reaction; INR was controlled monthly; CHA2DS2-VASC, HAS-BLED, SAMe-TT2R2 scale scores were evaluated; TTR was calculated using the Rosendaal method. Results. The distribution of CYP2C9, CYP4F2, VKORC1 genotypes in the main and control groups were in accordance with the Hardy–Weinberg equilibrium. In patients with AF and genotype-guided dosing, the frequency and risk of excessive hypocoagulation episodes (χ2 = 5.11; P < 0.05; RR = 0.50 (CI 0.27; 0.94)) and bleeding (χ2 = 9.57; P < 0.05; RR = 0.41 (CI 0.22; 0.77)) were significantly lower. However, the groups did not differ in TTR. The validity of genetic-guided dosing was confirmed by the comparability of the medians and the direct correlation between the calculated and therapeutic WF doses (r = +0.57; P < 0.05). There were no relationships between TTR, excessive hypocoagulation episodes, hemorrhagic complications and clinical and genetic factors in the main group. Conclusions. In patients with AF, the use of genotype-guided dosing method in the anticoagulant monitoring office helped to reduce the frequency and risk of excessive hypocoagulation episodes and bleeding as well as eliminate the influence of endogenous and exogenous factors in the personalized management of patients.

The aim. To investigate the influence of clinical and genetic factors on the stability of warfarin’s anticoagulant effect in patients with atrial fibrillation (AF) during the year. Materials and methods. The study involved 60 patients with AF, age 70.50 (64.25; 76.25) years (32 men and 28 women). Coagulogram indexes with International Normalized Ratio (INR) were determined using Coag Chrome 3003 monthly; the CHA2DS2-VASC, HAS-BLED, SAMe-TT2R2 scales scores were evaluated; the calculation of TTR was performed using the Rosendaal method. CYP2C9, CYP4F2, VKORC1 genes polymorphisms were determined using multiplex real time polymerase chain reaction in CFX-96 thermocycler (BioRad). Results. Median TTR in groups of patients with SAMe-TT2R2 score 0.05). There were significantly more patients with TTR 4) were detected in 21 (40 %) patients during the year. Excessive hypocoagulation was significantly more common in patients carrying the allele A of the VKORC1 gene in comparison with non-carriers (51.43 % versus 24.00 %; χ2 = 4.57, P < 0.05). The presence of mutant allele A was associated with 2.14-fold higher risk of excessive hypocoagulation (RR = 2.14; CI 1.06–4.69). Taking amiodarone (χ2 = 3.13; P < 0.05) had a significant effect on the development of excessive hypocoagulation with a relative risk RR = 1.83 (CI 1.01–3.35). Conclusions. SAMe-TT2R2 score can be useful to predict poor INR control, while VKORC1 genotype estimating – to predict excessive hypocoagulation episodes. An integrated approach using clinical and genetic methods is needed to determine the potential efficacy and safety of warfarin therapy.

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.

Background: The guide for the use of genotype-guided warfarin dosing in patients for the treatment of non-valvular atrial fibrillation (AF) is still lacking. Aim: We aimed to evaluate whether genotype-guided warfarin dosing is superior to conventional clinical dosing for the outcomes of interest in Chinese patients. Method: Our study consisted of 508 newly recruited and 471 existing Chinese AF patients. Among the total 979 patients, 585 patients received their dose of warfarin determined by a genetic and clinical factor (gene group), while the remaining 394 patients whose dosing was determined empirically in control group. We incorporated CYP2C9 and VKORC1 genotypes into the gene group. The international normalized ratio (INR) measurement and standard protocols were used for further dose adjustment in both groups. The primary outcomes were the percentage of time in the therapeutic range (%TTR) and INR during 12-month follow-up. Secondary safety outcome included bleeding and thrombotic events. Results: Compared with the control group, the average TTR of the gene group was higher [68.4 ± 20.6% vs 48.5 ± 21.6%, P < 0.001]. The average INR monitoring times to reach the therapeutic time in the gene group was lower (P < 0.001). The risk ratios (RR) for cumulative incidence of total bleeding events, minor bleeding events, gastrointestinal bleeding, and intracerebral bleeding events were not significantly different between the two groups (P > 0.05). Comparing to the analysis using existing 471 patients, the analysis using total 979 patients showed that the gene group experienced a lower (RR 0.4 (95% CI 0.2 to 0.8), P = 0.008) incidence of cumulative ischemic stroke. Conclusion: Genotype-guided warfarin administration increases the average TTR, reaches higher TTR levels in the early anticoagulant phase, and significantly reduces the risk of ischemic stroke events. [ABSTRACT FROM AUTHOR]

BACKGROUND: Resistance to rodenticides has been reported globally and poses a considerable problem for efficacy in pest control. The most‐documented resistance to rodenticides in commensal rodents is associated with mutations in the Vkorc1 gene, in particular in codon 139. Resistance to anticoagulant rodenticides has been reported in the Netherlands since 1989. A study from 2013 showed that 25% of 169 Norway rats (Rattus norvegicus) had a mutation at codon 139 of the Vkorc1 gene. To gain insight in the current status of rodenticide resistance amongst R. norvegicus and house mice Mus musculus in the Netherlands, we tested these rodents for mutations in codon 139 of the Vkorc1 gene. In addition, we collected data from pest controllers on their use of rodenticides and experience with rodenticide resistance. RESULTS: A total of 1801 rodent samples were collected throughout the country consisting of 1404 R. norvegicus and 397 M. musculus. In total, 15% of R. norvegicus [95% confidence interval (CI): 13–17%] and 38% of M. musculus (95% CI: 33–43%) carried a genetic mutation at codon 139 of the Vkorc1 gene. CONCLUSION: This study demonstrates genetic mutations at codon 139 of the Vkorc1 gene in M. musculus in the Netherlands. Resistance to anticoagulant rodenticides is present in R. norvegicus and M. musculus in multiple regions in the Netherlands. The results of this comprehensive study provide a baseline and facilitate trend analyses of Vkorc1 codon 139 mutations and evaluation of integrated pest management (IPM) strategies as these are enrolled in the Netherlands. © 2022 The Dutch Pest and Wildlife. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Purpose: Variants in CYP2C9 and VKORC1 genes have been associated with individuals' sensitivity to warfarin. The aim of this study was to investigate the differences of healthcare costs of genetically normal and genetically sensitive warfarin responder groups. Methods: This was a retrospective study linking genotype data from three Finnish biobanks (THL Biobank, Auria Biobank, Helsinki Biobank) with healthcare encounter data of the Finnish Institute of Health and Welfare (THL), drug dispensation data from the Social Insurance Institution of Finland (Kela) and laboratory data from Finnish hospital districts and municipalities. We compared the normal and sensitive warfarin responder groups in terms of healthcare costs related to bleeding and thromboembolic events, INR tests and medication purchases. Results: We found a trend towards increased bleeding‐related hospital costs in the sensitive warfarin responder group (881 patients) when compared with the normal responders (1627 patients) with a per patient difference of 150.9 €/year (95% CI: −55.1, 414.6 €/year, p = 0.087). INR test costs were higher in the sensitive responder group with a difference of 7.2 €/year (95% CI: −1.5, 16.4 €/year, p = 0.047). Medication costs were significantly lower in the sensitive responder group with a difference of −14.4 €/year (95% CI: −15.8, −12.9 €/year, p < 0.001). Conclusions: The difference in the costs of bleeding‐related hospitalization between genetically sensitive and normal warfarin responders may justify genotype‐guided warfarin dosing. Further studies with larger sample sizes would be needed to verify the result. [ABSTRACT FROM AUTHOR]

The vitamin K cycle, specifically the protein VKORC1 (Vitamin K epoxide reductase complex subunit 1), is closely linked to coagulation mechanisms in the body. Disruptions in this cycle will be associated with vascular diseases such as myocardial infarction and stroke. Warfarin is commonly used as an anticoagulant, but it still has side effects in interactions with numerous drug compounds; thus, it is necessary to search for safer candidate compounds. The ethanol extract of celery leaves (Apium graveolens L.) has potential anticoagulant activity, but the compound responsible for this activity has not been identified yet. The CADD method has been developed to predict in silico a compound's potential to interact with binding sites. This study aimed to predict interactions and obtain a stable complex of the compounds in the ethanol extract of celery leaves, which function as a VKORC1 antagonist. A total of 23 compounds were simulated using Autodock 4.2, and AMBER 18 was then used to simulate the stability of the five compounds with the best interactions. The docking simulation results of 17 test compounds (ligands) yielded five selected compounds, namely 6-isopentenyloxy-isobergapten (S1), Heratomin (S2), Apigenin (S3), Lanatin (S4), and Isoimperatorin (S5), with G values of −9.27, −9.26, −9.22, −9.13, and −8.94 kcal/mol, respectively. The MD simulation continued to produce 6-isopentenyloxy-isobergapten as the most effective ligand for stabilizing the complex for 100 ns from these five ligands. In conclusion, the 6-isopentenyloxy-isobergapten from celery leaf has the potential as a candidate anticoagulant, VKORC1. [ABSTRACT FROM AUTHOR]

Background: Anticoagulant rodenticides (ARs) are a very effective tool to control rodent pest populations. Nevertheless, AR resistance has been documented worldwide. ARs block the cycle of vitamin K, leading to the death of the animal by internal bleeding: mutations in Vkorc1 gene can cause resistance. The spreading of AR-resistant rodents could lead to an increase of their populations, the associated diffusion of zoonotic pathogens, and to the amplified exposure of non-target animals to ARs, thus it is important to study its diffusion widely. This study aimed to report firstly the presence of Vkorc1 mutations in synanthropic rodents from the Emilia-Romagna region, Italy, and evaluate their role in resistance by means of molecular docking analysis., Results: A total of 67 animals were analyzed: 24 Rattus norvegicus, 35 Rattus rattus and eight Mus musculus. Single nucleotide polymorphisms (SNPs) associated with AR resistance, in homozygosis or heterozygosis, were detected in 6/8 mice, on codons 128 and 139, and 13/24 R. norvegicus, on codons 61 and 139, and in 10/35 R. rattus, on codon 59. Furthermore, several newly described missense mutations were detected in all the tested species: the molecular docking analysis suggests a role of some of these (e.g., I123S and F87L) in resistance to brodifacoum, both in rats and in mice., Conclusion: The discovery of AR resistance SNPs in the 43.28% of tested rodents sounds as an alarm bell that requires the introduction of an integrated control approach, where ARs are not used routinely, but under specific monitoring evaluation. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

Introduction/Objective. Coumarin therapy represents one of the best models for applying pharmacogenetics. The contribution of factors influencing coumarin therapy can vary significantly between ethnic groups, which justifies conducting population-specific studies. The aim of this study was to analyze the influence of the most important genetic factors (VKORC1 and CYP2C9 genes) that affect coumarin therapy in patients from Serbia. Methods. A retrospective study involving 207 patients on acenocoumarol therapy was conducted. Genetic analyses were performed by direct sequencing. Influence on acenocoumarol dose of variants (VKORC1, CYP2C9*2, CYP2C9*3) causing hypersensitivity and VKORC1 variants causing resistance to acenocoumarol were analyzed. Multiple regression analysis was used to design a mathematical model for predicting individual drug dosage based on clinical-demographic and genetic data. Results. The study confirmed significant influence of the analyzed genetic factors on acenocoumarol maintenance dose. We designed mathematical model for predicting individual acenocoumarol dose and its unadjusted R2 was 61.8. In the testing cohort, our model gave R2 value of 42.6 and showed better prediction in comparison with model given by other authors. In the analyzed patients, nine different variants in the VKORC1 coding region were found. Among carriers of these variants 78% were completely resistant, and it was not possible to achieve therapeutic effect even with high doses of acenocoumarol. Conclusions. Population-specific model for prediction individual dose of acenocoumarol, may show advantages over protocols that are used in a generalized manner. Also, VKORC1 variants which cause coumarin resistance should be considered when planning therapy.

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 >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>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.

Background: Genetic polymorphisms of CYP2C9 and VKORC1 play a major role in pharmacokinetics and pharmacodynamics of coumarin anticoagulants. The purpose of our study was to assess the relative frequency of the above mutations in Bulgarian population in order to predict bleeding tendencies and precisely manage the anticoagulant therapy during the postoperative period after cardiac surgery with extracorporeal circulation. Methods: Genomic DNA samples from 200 Bulgarian patients subjected to cardiac surgery with extracorporeal circulation were analyzed for VKORC1 1639G>A and CYP2C9*2&*3 polymorphisms by real-time polymerase chain reaction (PCR), then allele frequencies of various genotypes were calculated by Hardy-Weinberg Equilibrium. Results: Median patients' age was 63.9 ± 10.8 years; 66.5% were male. Median BMI was 28.6 ± 5.4 kg/m2. Genotype distribution for CYP2C9 was *1/*1 - 51%, *1/*2 - 21%, *1/*3 - 13.5%, *2/*3 - 4%, *3/*3 - 2%, and *2/*2 - 1.5%. The calculated frequency of CYP2C9*1 allele was 74.25%, CYP2C9*2 allele was 13%, and CYP2C9*3 allele was 12.75%, and all allelic frequencies were in Hardy-Weinberg equilibrium (p-value = 0.358). The major VKORC1 genotype was G/A - 47%, followed by G/G - 35.5% and A/A - 17.5%). Based on Hardy-Weinberg Equilibrium, there was no significant difference between observed and expected frequencies (X - -3.779), presumably as a result of the homogeneity in the population. Conclusions: Analysis of the data obtained in the course of the study suggested that identification of homozygous carriers of VKORC1-1639 G>A (rs9923231) in Bulgarians may be useful in developing recommendations for personalized therapy. On the contrary, homozygous carriers of CYP2C9*2 or *3, included only 4.5% of the studied patients, thus indicating that this group would benefit less from dosing algorithms. Our results demonstrated good agreement with the results obtained in other studies conducted in the Caucasian population. [ABSTRACT FROM AUTHOR]

Background: Warfarin is the most widely used oral anticoagulant; nevertheless, dosing of warfarin is problematic for clinicians worldwide. Inter-individual variability in response to warfarin is attributed to genetic as well as non-genetic factors. Pharmacogenomics studies have identified variants in CYP2C9 and VKORC1 genes as significant predictors of warfarin dose, however, phenotypes of rare variants are not well characterized. Case presentation: We report a case of hyper-responsiveness to warfarin in a 22-year-old outpatient with Crohn's disease who presented with a swollen, red, and painful left calf. Deep venous thrombosis (DVT) in the left lower extremity was confirmed via ultrasonography, and hence, anticoagulation therapy of heparin and concomitant warfarin was initiated. Warfarin dose of 7.5 mg/day was estimated by the physician based on clinical factors. Higher than the expected international normalized ratio (INR) value of 4.5 necessitated the reduction of the warfarin dose to 5 and eventually to 2.5 mg/day to reach a therapeutic INR value of 2.6. Pharmacogenetic profiling of the VKORC1 -1639G > A and CYP2C9 *2, *3, *4, *5, *8, *14, *20, *24, *26, *33, *40, *41, *42, *43, *45, *46, *55, *62, *63, *66, *68, *72, *73 and *78 revealed a VKORC1-1639GA/CYP2C9*1*46 genotype. The lower catalytic activity of the CYP2C9*46 (A149T) variant was previously reported in in vitro settings. Conclusions: This is the first report on a case of warfarin hyper-responsive phenotype of a patient with the heterozygous CYP2C9*1*46 polymorphism. [ABSTRACT FROM AUTHOR]

To identify the impact of CYP2C9*2, *3, VKORC1−1639 G>A and CYP4F2*3 on warfarin dose in an Arab population. To compare the accuracy of a clinical warfarin dosing (CWD) versus genetic warfarin dosing algorithms (GWD) during warfarin initiation. A cohort of Arab patients newly starting on warfarin had their dose calculated using CWD published in www.warfarindosing.org and were followed for 1 month. Each patient provided a saliva sample. DNA was extracted, purified and genotyped for VKORC−1639 G>A, CYP2C9*2, CYP2C9*3 and CYP4F2*3. After reaching warfarin maintenance dose, the dose was recalculated using the GWD and median absolute error (MAE) and the percentage of warfarin doses within 20% of the actual dose were calculated and compared for the two algorithms. The study enrolled 130 patients from 12 Arabian countries. Compared to those with wild type, carriers of reduced function alleles in CYP2C9 required significantly lower median (IQR) warfarin weekly dose [24.5 (15.3) vs. 35 (29.8) mg/week, p=0.006]. With regards to VKORC , patients with AA genotype had a significantly lower median (IQR) weekly warfarin dose compared to AG and GG [21(10.5) vs 29.4 (21), p<0.001 for AA vs AG, p<0.001 for AA vs GG]. The MAE (IQR) for the weekly dose of the GWD was significantly lower compared to CWD [8.1 (10.5) vs 12.4 (12.6) (p<0.001)]. CYP2C9 and VKORC1 variants are important determinants of warfarin dose in the Arab population. The use of the genetic and clinical factors led to better warfarin dose estimation when compared to clinical factors alone. [ABSTRACT FROM AUTHOR]

Anna-Leena Vuorinen,1 Mika Lehto,2,3 Mikko Niemi,4,5 Kari Harno,6 Juha Pajula,1 Mark van Gils,1 Jaakko Lähteenmäki7 1VTT Technical Research Centre of Finland, Tampere, Finland; 2Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland; 3University of Helsinki, Helsinki, Finland; 4Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland; 5Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland; 6Department of Health and Social Management, University of Eastern Finland, Kuopio, Finland; 7VTT Technical Research Centre of Finland, Espoo, FinlandCorrespondence: Anna-Leena VuorinenVTT Technical Research Centre of Finland, P.O. Box 1300, Tampere, 33101, FinlandTel +358 40 8485966Email anna-leena.vuorinen@vtt.fiPurpose: To assess the association between VKORC1 and CYP2C9 variants and the incidence of adverse drug reactions in warfarin-treated patients in a real-world setting.Materials and Methods: This was a register-based cohort study (PreMed) linking data from Finnish biobanks, national health registries and patient records between January 1st 2007 and June 30th 2018. The inclusion criteria were: 1) ≥ 18 years of age, 2) CYP2C9 and VKORC1 genotype information available, 3) a diagnosis of a cardiovascular disease, 4) at least one warfarin purchase, 5) regular INR tests. Eligible individuals were divided into two warfarin sensitivity groups; normal responders, and sensitive and highly sensitive responders based on their VKORC1 and CYP2C9 genotypes. The incidences of clinical events were compared between the groups using Cox regression models.Results: The cohort consisted of 2508 participants (45% women, mean age of 69 years), of whom 65% were categorized as normal responders and 35% sensitive or highly sensitive responders. Compared to normal responders, sensitive and highly sensitive responders had fewer INR tests below 2 (median: 33.3% vs 43.8%, 95% CI: − 13.3%, − 10.0%) and more above 3 (median: 18.2% vs 6.7%, 95% Cl: 8.3%, 10.8%). The incidence (per 100 patient-years) of bleeding outcomes was 5.4 for normal responders and 5.6 for the sensitive and highly sensitive responder group (HR=1.03, 95% CI: 0.74, 1.44). The incidence of thromboembolic outcomes was 4.9 and 7.8, respectively (HR=1.48, 95% CI: 1.08, 2.03).Conclusion: In a real-world setting, genetically sensitive and highly sensitive responders to warfarin had more high INR tests and required a lower daily dose of warfarin than normal responders. However, the risk for bleeding events was not increased in sensitive and highly sensitive responders. Interestingly, the risk of thromboembolic outcomes was lower in normal responders compared to the sensitive and highly sensitive responders.Trial Registration: NCT04001166.Keywords: pharmacogenomics, warfarin, bleeding, INR, CYP2C9, VKORC1

Background: Warfarin is the most widely used oral anticoagulant for the prevention and treatment of thromboembolic disorders. Because of narrow therapeutic index and various genetic and non-genetic factors that influence the disposition of the drug, its dose undergoes a great variability. The aim of this study was to determine the allelic variants of CYP2C9 and VKORC1 genes in Iraqi patients, and to investigate the contribution of genetic on warfarin dose requirements.Methods: A cross sectional study was carried out on a sample of Iraqi patients from Baghdad city who were admitted to Ibn AL-Bitar Specialized Center for cardiac surgery. Blood samples of all patients were collected for both hematological and genetic analysis utilizing standard techniques.Results: The frequency of CYP2C9*3 allele was 9.4% whereas that of CYP2C9*2 allele was 13.7%. The frequency of (VKORC1-1639G) allele was 58.75% and the frequency of (VKORC1-1639A) allele was 41.25%. Patients’ daily warfarin doses were administered according to their genotype.Conclusion:It can be concluded that CYP2C9*3 and VKORC1 had significant effect on warfarin dose. New warfarin-dosing algorithm was developed based on CYP2C9*3 and VKORC1genotypes for predicting the required dose of warfarin.

Muhammad Salem,1 Islam Eljilany,2 Ahmed El-Bardissy,1 Hazem Elewa2,3 1Department of Pharmacy, Hamad General Hospital, Doha, Qatar; 2College of Pharmacy, QU Health, Qatar University, Doha, Qatar; 3Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, QatarCorrespondence: Ahmed El-BardissyDepartment of Pharmacy, Hamad General Hospital, PO Box 3050, Doha, QatarTel +974 5523 9167Email ahelbardissy@gmail.comAbstract: Warfarin–rifampin interaction has been reported since the 1970s. Due to rifampin’s strong induction of CYP2C9, most cases could not attain the target international normalized ratio (INR) despite warfarin dose escalation. Genetic polymorphisms determine up to 50% of warfarin dose variability. A 38-year-old woman was started on warfarin and rifampin for cerebral venous sinus thrombosis and pulmonary tuberculosis. Over six weeks, the daily warfarin dose was increased from 3 to 10 mg to attain three consecutive in-clinic therapeutic INRs. She completed three complications-free months of warfarin treatment with time in therapeutic range (TTR) of 46%. We performed retrospective genetic testing to determine the patient’s CYP2C9, CYP4F2, and VKORC1 genotypes and whether they had affected the interaction outcome. The analysis revealed that the subject carries CYP2C9*3*3 and VKORC1-1639 (GA) mutations, classifying her as a slow metabolizer and, hence, highly warfarin-sensitive. This was reflected on how the case responded to a relatively lower dose than previously reported cases that did not achieve the target on warfarin daily doses up to 35 mg. This is the first report addressing the genotype effect on this interaction. Patients with genetic variants requiring low warfarin doses are more likely to respond at a feasible dose while on rifampin. Future studies to evaluate warfarin–rifampin-gene interaction are warranted.Keywords: warfarin, rifampin, interaction, CYP2C9, VKORC1, genotype

BACKGROUND: Some rodent species living in arid areas show elevated physiological tolerance to anti‐vitamin K rodenticides (AVKs), which seems to be due to some unknown selective pressures that rodents may experience in desert habitats. Genes involved in the ϒ‐carboxylation of blood coagulation, including vitamin K epoxide reductase complex, subunit 1 (Vkorc1), ϒ‐glutamyl‐carboxylase (Ggcx) and NAD(P)H quinone one dehydrogenase (Nqo1) are associated with anticoagulant resistance, or some levels of elevated tolerance, in rodents. To detect whether the DNA sequences of the three genes are also under natural selection in the desert rodent species, we analyzed the Vkorc1, Ggcx and Nqo1 genes of the desert rodents and compared them with other rodent species. RESULTS: We found an accelerated evolutionary rate in Vkorc1 of desert rodents, especially in Mus spretus, Nannospalax galili and Psammomys obesus. By contrast, signals of positive selection were absent for Ggcx and Nqo1 in all species. Mapping the amino acid variations on the VKORC1 protein three‐dimensional model suggested most interspecific amino acid variations occur on the outer surface of the VKORC1 pocket, whereas most intraspecific amino acid changes and known AVK resistance mutations occurred on the inner surface and endoplasmic reticulum luminal loop regions. Some desert‐species‐specific amino acid variations were found on the positions where known resistance mutations occurred, indicating these variations might be related to the elevated physical tolerance to AVKs in desert rodents. CONCLUSION: The evolution of Vkorc1 has been accelerated in some desert rodent species, indicating genetic preadaptation to anticoagulant rodenticides. Positive selection and relaxed selection have been detected in Psammomys obesus and Nannospalax galili, indicating the two rodent species might also show tolerance to AVKs, which needs further verification. © 2022 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

BACKGROUND: Norway rats (Rattus norvegicus) need to be controlled to prevent transmission of pathogens and damages to stored products and material, leading to considerable economic risks and losses. Given increasing resistance in Norway rats, the most persistent, bio‐accumulative and toxic anticoagulant rodenticides are widely used for management, which presents hazards to the environment especially for non‐target species. We investigated how sanitary measures improved management of Norway rats on 12 paired livestock farms in a region of Germany with a high population of resistant rats for reducing application of rodenticides. We recorded food intake, and tracked activity and resistance frequency during the pre‐treatment, treatment and post‐treatment periods. RESULTS: In the post‐treatment period, farms using sanitary measures had a higher control success with > 13% more bait boxes without feeding than farms not using sanitary measures. In addition, the reoccurrence of rats was delayed by 85 days. With increasing accessibility to buildings and more precise positioning of the boxes, control success improved, especially when rats could not spread from water‐bearing ditches through the sewer system, and when rat‐hunting animals were present. Resistant animals were more common indoors than outdoors, and there were more resistant rats recorded before and during treatment than in the post‐treatment period. CONCLUSION: The control success was substantially higher and reoccurrence was delayed using sanitary measures on farms. Sanitary measures can reduce resistance indirectly due to delayed re‐colonization and establishment of resistant populations inside buildings. Hence, sanitary measures help to reduce economic losses, rodenticides required for rat management and environmental risk especially in the resistance area. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Warfarin has been widely used as an oral anticoagulant agent. In past, efforts have been done to study the contribution of genetic variation on warfarin dose requirements. The possible therapeutic dose determination of warfarin is very challenging, i.e., extremely low dose leading to unusable antithrombotic therapy or high dose causes particularly bleeding complications. Our study aimed to investigate these observations in more detail, we determined the correlation of interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α) among VKORC1 and CYP2C9 genetic variants in patients with heart valve replacement who were treated with a range of warfarin doses and compared with levels in healthy controls. A total of 107 human subjects were recruited with low < 5 mg, medium 5–10 mg/day, and high > 10 mg/day warfarin doses. The genetic study of VKORC1–1639G/A, C1173T, 3730G > A, CYP2C9*2, and CYP2C9*3 was performed using TaqMan genotyping and DNA sequencing. The gene expression of IL-6, TNF-α, and COX-2 mRNA was analyzed. IL-6, TNF-α, and COX-2 protein expressions were determined by ELISA and Western blot analysis to evaluate the pro- and anti-inflammatory effects of warfarin. A statistically significant difference was found among the haplotypes of VKORC1 rs9934438 (C1173T), rs9923231 (−1639G > A), rs7294 (3730G > A) and CYP2C9 *2 p. Arg144 Cys (rs28371674), CYP2C9 *3 p. Ile359Leu (rs1057910) genotypes with warfarin dose requirements (p = 0.001). The increased levels of COX-2, IL-6, and TNF-α proteins were observed when a high dose of warfarin (>10 mg/ml) was administered. However, a lower concentration (1.0 mg/ml) was observed with decreased warfarin dose (

Purpose: The purpose of this paper is to study the correlation between demographic and clinical factors and warfarin dose of patients in Chinese Han population taking warfarin and study gene polymorphisms impact of related gene loci (CYP2C9*3, VKORC1-1639G > A) on warfarin doses, to establish a model to predict initial standard dose and maintenance dose based on CYP2C9*3, VKORC1-1639G > A genotype. Methods: The study collects the data of patients in our hospital and other subcenters which incorporates 2160 patients to establish the initial dose model and 1698 patients for the stable dose model, and sequences 26 multigene sites in 451 patients. Based on the patient's dosage, clinical data, and demographic characteristics, the genetic and non-genetic effects on the initial dose and stable dose of warfarin are calculated by using statistical methods, and the prediction model of initial standard dose and maintenance dose can be established via multiple linear regression. Results: The initial dose of warfarin (mg/day) was calculated as (1.346 + 0.350 × (VKORC1-1639G > A) − 0.273 × (CYP2C9*3) + 0.245 × (body surface area) − 0.003 × (age) − 0.036 × (amine-iodine) + 0.021 × (sex))2. This model incorporated seven factors and explained 55.3% of the individualization differences of the warfarin drug dose. The maintenance dose of warfarin (mg/day) was calculated as (1.336 + 0.299 × (VKORC1-1639G > A) + 0.480 × (body surface area) − 0.214 × (CYP2C9*3) − 0.074 × (amine-iodine) − 0.003 × (age) − 0.077 × (statins) − 0.002 × (height))2. This model incorporated six factors and explained 42.4% of the individualization differences in the warfarin drug dose. Conclusion: The genetic and non-genetic factors affecting warfarin dose in Chinese Han population were studied systematically in this study. The pharmacogenomic dose prediction model constructed in this study can predict anticoagulant efficacy of warfarin and has potential application value in clinical practice. [ABSTRACT FROM AUTHOR]

Unrestricted use of anticoagulants has resulted in rodents developing resistance to them. This has caused a series of problems regarding reduction in rodent populations, which has further implicated great economic losses and a serious threat to the health of people and domestic animals. The popular global trend currently is to control rodent populations by applying the least possible amounts of chemicals, which on the other hand implies that several coactive alternative measures need to be applied in an eff ort to reduce rodent numbers to an acceptable economic level. On the other hand, knowledge of the genetic structure of rodent populations has become an important set of information desirable to have before setting off to apply rodenticides in practice, so as to prevent ineffective use of rodenticides and prevent further spreading of resistant rodent populations. The latest trend of using combinations of low-dose anticoagulant baits requires further research as their effects on susceptible populations are known but their impact on resistant animals is still not clear.

Objective To investigate the association between DNA methylation and the stable warfarin dose through genome-wide DNA methylation analysis and pyrosequencing assay. Method This study included 161 patients and genome-wide DNA methylation analysis was used to screen potential warfarin dose-associated CpGs through Illumina Infinium HumanMethylation 450 K BeadChip; then, the pyrosequencing assay was used to further validate the association between the stable warfarin dose and alterations in the methylation of the screened CpGs. GenomeStudio Software and R were used to analyze the differentially methylated CpGs. Results The methylation levels of CpGs surrounding the xenobiotic response element (XRE) within the CYP1A1 promoter, differed significantly between the different dose groups (P 0, P

BACKGROUND: Warfarin dosage regimens using CYP2C9 and VKORC1 polymorphisms have been extensively studied in adults and is included in US Food and Drug Administration-approved warfarin labeling. However, no dosage algorithm is available for pediatric patients. OBJECTIVE: To derive a genetics-based pediatric dosge regimen for warfarin, including starting dose and titration scheme. METHODS: A model-based approach was developed based on a previously validated warfarin dosage model in adults, with subsequent comparison to pediatric data from pediatric warfarin dose, genotyping, and international normalized ratio (INR) results. The adult model was based on a previously established model from the CROWN (CReating an Optimal Warfarin dosing Nomogram) trial. Pediatric warfarin data were obtained from a study conducted at the Childrens Hospital of Los Angeles with 26 subjects. Variant alleles of CYP2C9 (rs1799853 or *2, and rs1057910 or *3) and the VKORC1 single nucleotide polymorphism (SNP) rs9923231 (-1639 G>A) were assessed, where the rs numbers are reference SNP identification tags assigned by the National Center for Biotechnology Information. RESULTS: A pediatric warfarin model was derived using the previously validated model and clinical pharmacology considerations. The model was validated, and clinical trial simulation and stochastic modeling were used to optimize pediatric dosage and titration. The final dosage regimen was optimized based on simulations targeting a high (≥60%) proportion of INRs within the therapeutic range by week 2 of warfarin therapy while minimizing INRs >3.5 or A) genotypes may offer improved dosage compared to current treatment strategies, especially in patients with variant CYP2C9 and VKORC1 alleles. This pilot study provides the foundation for a larger prospective evaluation of genetics-based warfarin dosage in pediatric patients.

Warfarin is a readily available anticoagulant used worldwide in a variety of clinical scenarios. Patients who need more than 15 mg/day are considered to be warfarin resistant. Numerous genes have been implicated in warfarin pharmacogenetics, with genes encoding CYP2C9 and VKORC1 shown to be the most important determinants of drug dosage requirements. A 27-year-old woman was admitted as she had a sub-therapeutic international normalized ratio (INR) after prosthetic mitral valve replacement. Even after a warfarin dose of 50 mg/day, her INR was not in the therapeutic range, so the heart team decided to replace her metallic valve with a bioprosthetic valve, thus alleviating the need for anticoagulation.

Abstract Background Genotype-guided warfarin dosing has been shown in some randomized trials to improve anticoagulation outcomes in individuals of European ancestry, yet its utility in Asian patients remains unresolved. Methods An open-label, non-inferiority, 1:1 randomized trial was conducted at three academic hospitals in South East Asia, involving 322 ethnically diverse patients newly indicated for warfarin (NCT00700895). Clinical follow-up was 90 days. The primary efficacy measure was the number of dose titrations within the first 2 weeks of therapy, with a mean non-inferiority margin of 0.5 over the first 14 days of therapy. Results Among 322 randomized patients, 269 were evaluable for the primary endpoint. Compared with traditional dosing, the genotype-guided group required fewer dose titrations during the first 2 weeks (1.77 vs. 2.93, difference −1.16, 90% CI −1.48 to −0.84, P

Abstract Background The anticoagulation of atrial fibrillation catheter ablation during the perioperative stage does matter and should be treated with discretion. We aimed to assess impact of three important genes participating in vitamin K cycle (i.e. VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566) on the daily stable warfarin dose requirement in Sichuan Han Chinese patients with catheter ablation of atrial fibrillation. Methods A total of 222 atrial fibrillation patients taking stable warfarin therapy after catheter ablation operation were enrolled in this study. The study population included had high (≥2) risk according to the CHA2DS2-VASc risk score. Genotypes of VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566 were analyzed by using the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP). Multiple linear regression analysis was applied to depict the impact of VKORC1 rs9923231, CYP4F2 rs2108622 and NQO1 rs1800566 on the daily stable warfarin dose requirement. Results Carriers of VKORC1 rs9923231 AG/GG genotypes required significantly higher warfarin dose (3.03 ± 0.28 mg/day, 7.19 mg/day, respectively) than AA carriers (2.52 ± 0.07 mg/day; P