VKORC1 Genetic Polymorphisms Research Articles

Association between CYP2C9 and VKORC1 genetic polymorphisms and efficacy and safety of warfarin in Chinese patients.

Genetic variation has been a major contributor to interindividual variability of warfarin dosage requirement. The specific genetic factors contributing to warfarin bleeding complications are largely unknown, particularly in Chinese patients. In this study, 896 Chinese patients were enrolled to explore the effect of CYP2C9 and VKORC1 genetic variations on both the efficacy and safety of warfarin therapy. Univariate analyses unveiled significant associations between two specific single nucleotide polymorphisms rs1057910 in CYP2C9 and rs9923231 in VKORC1 and stable warfarin dosage (P < 0.001). Further, employing multivariate logistic regression analysis adjusted for age, sex and height, the investigation revealed that patients harboring at least one variant allele in CYP2C9 exhibited a heightened risk of bleeding events compared to those with the wild-type genotype (odds ratio = 2.16, P = 0.04). Moreover, a meta-analysis conducted to consolidate findings confirmed the associations of both CYP2C9 (rs1057910) and VKORC1 (rs9923231) with stable warfarin dosage. Notably, CYP2C9 variant genotypes were significantly linked to an increased risk of hemorrhagic complications (P < 0.00001), VKORC1 did not demonstrate a similar association. The associations found between specific genetic variants and both stable warfarin dosage and bleeding risk might be the potential significance of gene detection in optimizing warfarin therapy for improving patient efficacy and safety.

Efficacy of Warfarin Therapy Guided by Pharmacogenetics: A Real-world Investigation Among Han Taiwanese

The anticoagulation activity of warfarin in populations with CYP2C9, VKORC1, and CYP4F2 variants differs between individuals and is correlated with poor international normalized ratio (INR) control. Pharmacogenetics-guided warfarin dosing has been successfully developed for patients with genetic variations in recent years. However, few real-world data have been used to investigate the INR and warfarin dosage and the time to target INR. This study examined the largest collection of genetic and clinical real-world data related to warfarin to provide further evidence supporting the benefits of pharmacogenetics in clinical outcomes. We retrieved a total of 69,610 INR-warfarin records after the index date from 2,613 patients in the China Medical University Hospital database between January 2003 and December 2019. Each INR reading was obtained from the latest laboratory data after the hospital visit date. Patients with a history of malignant neoplasms or pregnancy before the index date were excluded, as were patients without data on INR measurements after the fifth day of prescription, genetic information, or gender variables. The primary outcomes were the INR and warfarin dosage during days 7, 14, 28, 56, and 84 after prescription. The secondary outcome was the time required to reach the INR ranges of 1.5 to 3.0 and >4.0. A total of 59,643 INR-warfarin records from 2188 patients were retrieved. The average INR was higher for homozygous carriers of the minor allele at CYP2C9 and VKORC1 during the first 7 days (1.83 [1.03] [CYP2C9*1] and 2.46 [1.44] [CYP2C9*3], P < 0.001; 1.39 [0.36] [rs9923231 G/G], 1.55 [0.79] [rs9923231 G/A], and 1.96 [1.13] [rs9923231 A/A], P < 0.001) than for the wild-type allele. These patients with variants required lower warfarin doses than those with the wild-type allele during the first 28 days. CYP4F2 variant patients seemed to require higher doses of warfarin than those in the wild-type group; however, no significant difference in the average INR was observed (1.95 [1.14] [homozygous V433 carriers], 1.78 [0.98] [heterozygous V433M carriers], and 1.66 [0.91] [homozygous M433 carriers], P=0.016). Our study indicates that genetic variants in the Han population may enhance warfarin responsiveness, which holds clinical relevance. An increased warfarin dosage was not linked to a shorter time to therapeutic INR between CYP4F2 variant patients and those with a wild-type allele. Assessing CYP2C9 and VKORC1 genetic polymorphisms before initiating warfarin treatment in real-world practice is essential for potentially vulnerable patients and is likely to optimize therapeutic dosing.

Platelet and coagulation hemostasis status in patients with atrial fibrillation depending on warfarin dosing method

The aim. To evaluate indicators of induced platelet aggregation and D-dimer level in patients with atrial fibrillation (AF) depending on the method of warfarin (WF) dosing. Materials and methods. The study involved 110 patients with AF (mean age 68.72 ± 0.79; men – 57, women – 53). 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 traditional dosing method. CYP2C9, CYP4F2, VKORC1 genetic polymorphisms were determined using multiplex real time polymerase chain reaction, D-dimer concentration – by the method of solid-phase enzyme immunoassay; ADP- and epinephrine-induced aggregation indicators – by the method of G. Born. Results. The percentage (by 24 %), time (by 3 min 6 s) and rate in 30 s (by 19.5 %/min) of ADP-induced platelet aggregation were significantly lower in patients with AF and genotype-guided WF dosing method. D-dimer concentration in patients of the main and control groups did not differ significantly. However, significantly fewer patients with elevated D-dimer values were registered in the group with genotype-guided WF dosing method compared to the group with traditional dosing method: 0 (0.00 %) vs. 7 (11.67 %) at 500 ng FEU/ml cut-off (χ2 = 4.43, P &lt; 0.05), 1 (2.00 %) vs. 9 (15.00 %) at 390 ng FEU/ml cut-off (χ2 = 4.16, P &lt; 0.05), 0 (0.00 %) vs. 7 (11.67 %) at age-adjusted cut-off (χ2 = 4.43, P &lt; 0.05). Conclusions. The obtained results may indicate a potentially lower risk of thrombotic events in patients with AF and genotype-guided WF dosing method compared to the group with traditional dosing method, which confirms the benefit of the widespread use of the pharmacogenetic testing in clinical practice.

Influence of CYP2C9, VKORC1, and CYP4F2 polymorphisms on the pharmacodynamic parameters of warfarin: a cross-sectional study.

Warfarin is the most commonly evaluated drug in pharmacogenetic-guided dosing studies. However, gaps remain regarding the influence of the genetic polymorphisms of CYP2C9, VKORC1, and CYP4F2 on specific pharmacodynamic parameters like the warfarin sensitivity index (WSI), prothrombin time international normalized ratio (PT-INR), and log-INR variability. A cross-sectional study was conducted in non-smoking adults receiving warfarin for at least 6months. Their demographics, diagnoses, warfarin dosing regimen, concomitant drugs, PT-INR, and bleeding episodes were obtained. CYP2C9 (rs1057910-*3 and rs1799853-*2 alleles), CYP4F2 (rs2108622), and VKORC1 (rs9923231) polymorphisms were assessed using real-time polymerase chain reaction. Three genotype groups (I-III) were defined based on the combined genetic polymorphisms of CYP2C9 and VKORC1 from the FDA's recommendations. Key outcome measures included anticoagulation control, time spent in therapeutic range, stable warfarin dose, WSI, log-INR variability, and Warfarin Composite Measure (WCM). The study recruited 236 patients; 75 (31.8%) carried a functional CYP2C9 variant allele, and, 143 (60.6%) had at least one T allele in CYP4F2 and 133 (56.4%) had at least one T allelein VKORC1. Groups' II and III CYP2C9 and VKORC1 genotypes were observed with reduced stable warfarin dose, increased WSI, higher log-INR variability, and increased bleeding risk. The presence of *2 or *3 allele in CYP2C9 was observed with reduced stable warfarin doses akin to the presence of T alleles in VKORC1; however, the doses increased with T alleles in CYP4F2. The evaluated genetic polymorphisms significantly influenced all the pharmacodynamic parameters of warfarin. Evaluating CYP2C9, VKORC1, and CYP4F2 genetic polymorphisms prior to warfarin initiation is likely to optimize therapeutic response.

The impact of CYP2C9 and VKORC1 genetic polymorphisms in anticoagulant therapy management after cardiac surgery with extracorporeal circulation

Extracorporeal circulation during cardiac surgery is characterized with increased risk for hypercoagulation because blood is exposed to foreign, nonendothelial cell surfaces. Thus, the usage of extracorporeal circulation is essentially not possible without anticoagulation. Open-heart surgery as well as many perioperative factors, such as acidosis, hypocalcemia, hypothermia, and hemodilution, might affect hemostasis and lead to coagulopathy and bleeding. A new insight into the effectiveness of anticoagulant therapy is applied to modify the dosing regimen with respect to the genetic CYP2C9 and VKORC1allelic variants. A systematic literature search was performed for VKORC1 and CYP2C9 and their association with coumarin anticoagulant therapy and bleeding risk in postoperative period of cardiac surgery with extracorporeal circulation.

Cytochrome p-450 and VKORC1 genetic polymorphisms in nenets - an indigenous ethnic group in the Arctic

Resilience of indigenous ethnic groups to adverse climatic conditions of the Arctic is genetically determined. Moreover, genes determine the ability to metabolize environmental substances. This warrants research on ethnic variations in cytochrome P-450 and VKORC1 genetic polimorphisms with further going aim to develop personalized pharmacotherapy for the indigenous ethnic groups living in the Arctic. The aim was to study the prevalence of genotypes and allelic variants in CYP2C9, CYP2C19, VKORC1 genes in Nenets - an indigenous ethnic group in the Arctic. (n = 32) under conditions of permanent island living. Methods. A total population (n = 32) of the Vaygach island (70°01' N 59°33' E) participated in a cross-sectional study. Peripheral venous blood samples were taken. Genomic DNA was extracted from peripheral venous blood leukocytes using the express method. Results. SS genotype was the most common variant (90.63 %) of the CYP2C9*2 (rs1799853) gene. AA genotype of the CYP2C9*3 (rs1057910) gene was detected in 100 % cases. GG and GA genotypes of the VKORC1 G3730A (rs7294) gene were detected in 56.3 % and 43.7 % of cases, respectively, while no homozygous allelic polymorphism for the pathological allele was found. Conclusions. The study provides the evidence on the prevalence of genotypes and allelic variants in CYP2C9, CYP2C19, VKORC1 genes in Nenets of the Vaygach island. Replication of these results in other Nenets populations is warranted.

Effects of CYP2C9 and VKORC1 genetic polymorphisms in Chinese Han population on maintenance dosage of warfarin

Objective To analyze CYP2C9 and VKORC1 gene polymorphisms in Chinese Han population and their correlation with the maintenance dosage of warfarin. Methods From October 2017 to April 2018, 458 Chinese Han patients (213 males and 245 females, aged from 26 to 94 years old) who underwent coagulation analysis in Peking University People′s Hospital were included in this retrospective study. PCR-Fluorescent probe method was applied to detect CYP2C9*3 and VKORC1-1639A>G gene polymorphisms in 458 patients, and among them, 130 patients who took warfarin for anticoagulant therapy and reached the international standard ratio of prothrombin time (INR) within the range of 2.0-3.0 were recorded. The basic information, dosage of warfarin and INR were also recorded. The statistical analysis data were compared with the reference table of recommended dosage of warfarin for different genotypes of patients recommended by FDA and the formula of predicted dosage of warfarin was simply verified by SPSS. Results Among the 458 patients who took anticoagulant therapy, the genotype frequencies of CYP2C9*1/*1(AA), CYP2C9*1/*3(AC) and CYP2C9*3/*3(CC) were 90.8%, 8.5%, and 0.7%; the genotype frequencies of VKORC1-1639GG and VKORC1-1639AG were 0.9% and 14.2%; the genotype frequencies of VKORC1-1639AA was 84.9%. After INR was reached, the results showed that the variant CYP2C9*1/*3 and CYP2C9*3/*3 required lower daily maintain dosage [(2.92±1.29) mg] than wild-type CYP2C9*1/*1 patients did [(3.91±1.63) mg], with statistically significant difference (P=0.018). And variant VKORC1-AA required lower daily maintain dosage [(3.68±1.64) mg] than variant VKORC1-AG patients did [(4.54±1.29) mg], with statistically significant difference (P=0.001). The application dosage of warfarin in patients with different VKORC1+CYP2C9 genotypes was consistent with the recommended dosage of the FDA reference table. The prediction accuracy of miao 2007 formula was lower than that of IWPC formula, and 94.1% of patients′ dosages of warfarin were underestimated. Conclusion Patients with CYP2C9*3 or VKORC1-AA genotype required lower warfarin dosage. The CYP2C9 and VKORC1 gene polymorphisms had a certain correlation with maintenance dosage of warfarin. Key words: Warfarin; Polymorphism, genetic; Cytochrome P-450 CYP2C9; Vitamin K epoxide reductases; Dose-respanse relationship,drug

The impact of R353Q genetic polymorphism in coagulation factor VII on the initial anticoagulant effect exerted by warfarin.

The initial rise in INR following warfarin is attributed to rapid decline in coagulation factor VII (F7). The R353Q polymorphism in F7 accounts for approximately 1/3 of the variability in F7 activity (FVIIc). Evaluate the role of R353Q in the initial response to warfarin. Twenty-eight healthy, males, carrying CYP2C9*1/*1 (n = 14), CYP2C9*1/*2 (n = 4) or CYP2C9*1/*3 (n = 10) genotypes, received single 20mg warfarin. S&R-warfarin concentrations, INR, and FVIIc were monitored periodically for 7days. Baseline and maximal INR were 5.6% and 33.5% higher among carriers of the RQ (n = 12) as compared with those carrying the RR (n = 16) genotype (p = 0.032, p = 0.003, respectively). Baseline and nadir FVIIc were 21.6% and 42.0% lower among subjects carrying the RQ as compared with carriers of the RR genotype (p = 0.001, p = 0.007 respectively). In multiple regression analysis, R353Q predicted 36.6% of the variability in peak INR whereas 20.2%, 9.9%, and 5.9% were attributed to VKORC1 genetic polymorphism, cholesterol concentration, and S Warfarin concentration after 24h, respectively. R353Q genetic polymorphism plays a key role in determining the initial response to warfarin. The incorporation of this genetic variant into warfarin loading algorithm should be further investigated.

A multi-factorial analysis of response to warfarin in a UK prospective cohort.

BackgroundWarfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin.MethodsA prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R.ResultsVKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C9*3, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role.ConclusionOur multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0255-y) contains supplementary material, which is available to authorized users.

The effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirements in a pediatric population

The effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirements in a pediatric population

Effect of CYP2C9, CYP4F2 and VKORC1 genetic polymorphisms on pharmacokinetics and pharmacodynamics of mean daily maintenance dose of warfarin in Chinese patients.

In this study, we studied the effects of different genetic variants of CYP2C9, VKORC1 and CYP4F2, and clinical factors on the concentration levels of S-warfarin (WF), R-WF and S, R-7-OH-WF, as well as the mean daily maintenance dose of warfarin in 211 patients on warfarin therapy for at least 3 months. The genotypes of single nucleotide polymorphism (SNP), CYP2C9, VKORC1 1173C>T and CYP4F2 were identified by PCR. Plasma concentrations of S-WF and R-WF and S-7-OH-WF, R-7-OH-WF were determined by high-performance liquid chromatography tandem mass spectrometry on chiral columns. The warfarin dosage requirement correlated negatively with age and was in direct proportion to body weight. VKORC1 1173CC carrier had significantly lower dosage requirements than that with the heterozygous VKORC1 1173CT genotype. The concentration of both 7-OH-S-WF and 7-OH-R-WF, and the warfarin dose showed a significant difference. There were significant differences in the concentrations of S-WF and 7-OH-S-WF among the CYP2C9 variants. The concentration of warfarin, 7-OH-WF and warfarin maintenance dose were not affected by the CYP4F2 V433M variant. In conclusion, VKORC1 1173C>T genotype correlates strongly with a lower daily warfarin dose and the concentration of S-7-OH, R-7-OH warfarin in Han Shanghainese patients. In addition, the results not only demonstrated the effect on pharmacodynamics of warfarin, but also enhanced the enzymatic activity of CYP450 to influence the pharmacokinetic of warfarin.

VKORC1 and CYP2C9 genotypic data-based dose prediction alone does not accurately predict warfarin dose requirements in some Malaysian patients.

VKORC1 and CYP2C9 genetic polymorphisms may not accurately predict warfarin dose requirements. We evaluated an existing warfarin dosing algorithm developed for Malaysian patients that was based only on VKORC1 and CYP2C9 genes. Five Malay patients receiving warfarin maintenance therapy were investigated for their CYP2C9*2, CYP2C9*3, and VKORC1-1639G>A genotypes and their vitamin K-dependent (VKD) clotting factor activities. The records of their daily warfarin doses and international normalized ratio (INR) 2 years prior to and after the measurement of VKD clotting factors activities were acquired. The mean warfarin doses were compared with predicted warfarin doses calculated from a genotypic-based dosing model developed for Asians. A patient with the VKORC1-1639 GA genotype, who was supposed to have higher dose requirements, had a lower mean warfarin dose similar to those having the VKORC1-1639 AA genotype. This discrepancy may be due to the coadministration of celecoxib, which has the potential to decrease warfarins metabolism. Not all patients' predicted mean warfarin doses based on a previously developed dosing algorithm for Asians were similar to the actual mean warfarin dose, with the worst predicted dose being 54.34% higher than the required warfarin dose. Multiple clinical factors can significantly change the actual required dose from the predicted dose from time to time. The additions of other dynamic variables, especially INR, VKD clotting factors, and concomitant drug use, into the dosing model are important in order to improve its accuracy.

Polymorphism in vkorc1 Gene of Natal Multimammate Mice, Mastomys natalensis, in Tanzania.

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

An acenocoumarol dosing algorithm exploiting clinical and genetic factors in South Indian (Dravidian) population

The objective of this study was to determine the influence of CYP2C9, VKORC1, CYP4F2, and GGCX genetic polymorphisms on mean daily dose of acenocoumarol in South Indian patients and to develop a new pharmacogenetic algorithm based on clinical and genetic factors. Patients receiving acenocoumarol maintenance therapy (n = 230) were included in the study. Single nucleotide polymorphisms (SNP) of CYP2C9, VKORC1, CYP4F2, and GGCX were genotyped by real-time polymerase chain reaction (RT-PCR) method. The mean daily acenocoumarol maintenance dose was found to be 3.7 ± 2.3 (SD) mg/day. The CYP2C9 *1*2, CYP2C9 *1*3, and CYP2C9 *2*3 variant genotypes significantly reduced the dose by 56.7 % (2.0 mg), 67.6 % (1.6 mg), and 70.3 % (1.5 mg) than wild-type carriers 4.1 mg, p < 0.0001. The genetic variants of CYP2C9 and GGCX (rs11676382) were found to be associated with lower acenocoumarol dose, whereas CYP4F2 (rs2108622) was associated with higher doses. Age, body mass index (BMI), variation of CYP2C9, VKORC1, CYP4F2, and GGCX were the major determinants of acenocoumarol maintenance dose, accounting for 61.8 % of its variability (adjusted r (2) = 0.615, p < 0.0001). Among the VKORC1 variants, rs9923231 alone contributed up to 28.6 % of the acenocoumarol dose variation. VKORC1 rs9923231 polymorphism had the highest impact on acenocoumarol daily dose. A new pharmacogenetic algorithm was established to determine the acenocoumarol dose in South Indian population.

Role of CYP2C9, VKORC1 and Calumenin Genotypes in Monitoring Warfarin Therapy: An Egyptian Study

Background: Oral anticoagulant therapy is conditioned by environmental and genetic factors.Objectives: To verify the effect of the calumenin, cytochrome P-450 variants and VKORC1 genetic polymorphisms on the response to warfarin therapy and warfarin dose adjustment.Patients and Methods: We selected fifty warfarin treated patients with dose adjusted at INR value between 2 and 3. PCR-RFLP is used for of calumenin gene polymorphism. Insitu Hybridization was used for identification of VKORC1 promoter and CYP2C9 variants polymorphisms.Results: The warfarin dose in the patients with Calumenin and CYP2C9 genetic polymorphism was lower than the wild type gene. The warfarin dose in the patients with VKORC1 variants was statistically lower compared to that of the wild-type. The presence of combined CYP2C9 genetic variants and VKORC1 polymorphism was associated with lower warfarin dose than that the wild types.Conclusion: Calumenin (CALU) might be a new genetic factor involved in the pharmacogenetics of anticoagulant therapy.

Role of CYP2C9, VKORC1 and Calumenin Genotypes in Monitoring Warfarin Therapy: An Egyptian Study

Background: Oral anticoagulant therapy is conditioned by environmental and genetic factors.Objectives: To verify the effect of the calumenin, cytochrome P-450 variants and VKORC1 genetic polymorphisms on the response to warfarin therapy and warfarin dose adjustment.Patients and Methods: We selected fifty warfarin treated patients with dose adjusted at INR value between 2 and 3. PCR-RFLP is used for of calumenin gene polymorphism. Insitu Hybridization was used for identification of VKORC1 promoter and CYP2C9 variants polymorphisms.Results: The warfarin dose in the patients with Calumenin and CYP2C9 genetic polymorphism was lower than the wild type gene. The warfarin dose in the patients with VKORC1 variants was statistically lower compared to that of the wild-type. The presence of combined CYP2C9 genetic variants and VKORC1 polymorphism was associated with lower warfarin dose than that the wild types.Conclusion: Calumenin (CALU) might be a new genetic factor involved in the pharmacogenetics of anticoagulant therapy.

Effect of CYP2C9 and VKORC1 genetic polymorphisms on mean daily maintenance dose of acenocoumarol in South Indian patients

AimTo determine the effect of CYP2C9 and VKORC1 genetic polymorphisms on mean daily maintenance dose of acenocoumarol in South Indian patients with heart valve replacement. Materials and methodsThe study was conducted in 170 patients on therapy with acenocoumarol following heart valve replacement surgery. Single nucleotide polymorphisms (SNP) namely CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), and VKORC1 (rs9923231) were identified by quantitative Real-Time Polymerase Chain Reaction (RT-PCR) method. ResultsPatients with at least one variant allele of CYP2C9 (*1*2 or *1*3) required 44% and 28.2% lower daily maintenance dose of acenocoumarol (2.0mg and 2.5mg, respectively) than the normal CYP2C9*1*1 genotype group (3.4mg) (p<0.05). Patients with VKORC1 GG genotype required higher dose (3.3mg) as compared to those with genotype VKORC1 GA (2.3mg) and VKORC1 AA (1.0mg) (p<0.001). Patients with both CYP2C9*1*2/*1*3 and VKORC1 GA genotype required 38% lower dose (2.46mg) than patients with CYP2C9*1*1 and VKORC1 GG genotype (3.52mg) (p<0.0001). The clinical (age, body mass index) and genetic variables (VKORC1-1639 G>A, CYP2C9*2, CYP2C9*3) contribute together to predict 30.4% of the required maintenance dose of acenocoumarol. ConclusionThe genetic polymorphisms of CYP2C9 and VKORC1 results in decreased requirement of daily maintenance dose of acenocoumarol. The polymorphism VKORC1 (–1639 G>A) was found to be the major predictor of acenocoumarol dose requirement in South Indian population.

Influence of CYP4F2 Polymorphisms and Plasma Vitamin K Levels on Warfarin Sensitivity in Japanese Pediatric Patients

The aim of this study was to reveal the contribution of CYP4F2, CYP2C9, and VKORC1 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of warfarin in Japanese pediatric patients. Genetic analyses of CYP4F2 (rs2108622), CYP2C9 (*2 and *3), and VKORC1 (-1639G>A) were performed, and plasma unbound warfarin, vitamin K1 (VK1), and menaquinone-4 (MK-4) concentrations were determined in 37 Japanese pediatric patients. The patients with CYP4F2 variant alleles C/T and T/T scored significantly lower values for the warfarin sensitivity index (INR/Cpss) and had significantly higher plasma concentrations of MK-4 than patients with the CYP4F2 allele C/C. Moreover, the plasma MK-4 concentration was negatively correlated with the warfarin sensitivity index. In contrast, the VKORC1 genetic polymorphism did not influence the warfarin sensitivity index. In patients with the CYP2C9 *3 allele, the unbound oral clearance values (normalized to body surface area) for S-warfarin were found to be significantly lower than in patients with the wild-type allele. In conclusion, CYP4F2 genetic polymorphism and plasma MK-4 concentration influence the pharmacodynamics of warfarin, suggesting a mechanism though which CYP4F2 genotype affects warfarin dose.

VKORC1 rs2359612C allele is associated with increased risk of coronary artery disease in the presence of coronary calcification

VKORC1 genetic polymorphisms affect warfarin dose response, aortic calcification, and the susceptibility of coronary artery disease as shown in our previous study. Little is known regarding the association of VKORC1 polymorphisms with coronary artery calcification (CAC) and the role of CAC in the association with coronary artery disease (CAD). Due to a natural haplotype block in the VKORC1 gene in Chinese, polymorphism rs2359612 was analyzed in a case-control study and a prospective study. The case-control study included 464 CAD patients with non-calcified plaque (NCP), 562 CAD patients with mixed calcified plaque (MCP), 492 subjects with calcified plaque (CP), and 521 controls. The rs2359612C was only associated with increased risk of MCP, the CAD in the presence of CAC; the odds ratio was 1.397 (95 % CI 1.008-1.937, P < 0.05), which was replicated in the second independent population. On the contrary, a negative correlation was observed between rs2359612 and log-transformed Agatston score, and rs2359612 was negatively associated with the number of calcified vessels. Moreover, in a prospective study including 849 CAD patients undergoing revascularization, rs2359612C predicted a higher incidence of cardiovascular events in MCP subgroup; the relative risk was 1.435 (95 % CI 1.008-2.041, P = 0.045), which was not observed in the NCP subgroup. We conclude that the rs2359612C was associated with a higher risk of CAD in the presence of CAC and a higher incidence of cardiovascular events in CAD patients with CAC, but a lower coronary calcification. VKORC1 polymorphisms may be associated with the endophenotype of CAD, calcification-related atherosclerosis.

Frequency of VKORC1 (C1173T) and CYP2C9 genetic polymorphisms in Egyptians and their influence on warfarin maintenance dose: proposal for a new dosing regimen

Warfarin is one of the most widely used anticoagulants, yet interindividual differences in drug response, a narrow therapeutic range and a high risk of bleeding or stroke complicate its use. We aimed to determine the allele and genotype frequency of VKORC1 1173 C>T, CYP2C9*2 and CYP2C9*3 variant polymorphisms in the Egyptian population and to evaluate their influence on the interindividual differences in warfarin dosage. A total of 154 unrelated healthy adult patients and 46 warfarin-treated patients were included. SYBR Green-based real-time polymerase chain reaction (PCR) assay was used for studying VKORC1 (C1173T) and CYP2C9*3 polymorphisms. Mutagenically separated PCR assay was used to detect the CYP2C9*2 allele. VKORC1 genotype frequencies were 11%, 24% and 65% for CC, CT and TT, respectively. The prevalence of CYP2C9 haplotypes was 81% (*1\*1), 3.3% (*1\*2), 9.7% (*1\*3), 4.5% (*2\*2) and 0.65% (2\*3 and *3\*3). VKORC1 TT and CYP2C9*2\*2 were associated with a significantly lower warfarin dose. VKORC1 and CYP2C9 accounted for 31.7% and 15.6% of warfarin dose variability, respectively, and together with clinical factors explained 61.3% of total variability. VKORC1-TT and CYP2C9 *1/*1 are the most prevalent genotypes among Egyptians. Patients with VKORC1-TT genotype required a lower warfarin dose.