VKORC1 Polymorphisms Research Articles

NEW APPROACHES TO INDIVIDUALIZED CHOICE OF ORAL ANTICOAGULANTS IN PATIENTS WITH ATRIAL FIBRILLATION

Aim. To evaluate adherence to treatment, mutations of the hemostatic system and food preferences as predictors of choice of optimal anticoagulant therapy in patients with atrial fibrillation (AF). Material and methods . 142 patients with AF were quantitatively evaluated in terms of their adherence to treatment, polymorphism of genes CYP2C9 and VKORC1 and the structure of food preferences. Results . Persons with insufficient adherence to treatment prevailed among AF patients, at that the leading negative factor was the low adherence to medical support, which directly related with the frequency of complications and ineffectiveness of anticoagulant therapy. The very high prevalence of gene mutations CYP2C9 and VKORC1 (more than 2.3 per 1 respondent) was detected in the study sample, which makes screening pharmacogenetic testing ineffective and is an independent risk factor for the Omsk region. Consumption by the population of food products that can affect anticoagulant therapy with warfarin does not have special regional characteristics and does not differ significantly among respondents both without AF and with AF (99.2±41.9 vs 100.8±38.6 points; р=0.82) as well as among patients with AF both taking and not taking warfarin (85.4±47.0 vs 107.3±42.1 points, p=0.9). Conclusion . Individualized choice of anticoagulant in patients with AF should be based on a structured quantitative assessment of adherence to treatment. In low adherence to treatment and choice of warfarin as an anticoagulant, its safety should be confirmed by the assessment of pharmacogenetic status and/or dietary preferences of the patient.

Association between genetic polymorphisms of CYP2C9 and VKORC1 and safety and efficacy of warfarin: Results of a 5 years audit

ObjectiveGenetic polymorphisms of CYP2C9 and VKORC1 play major role in pharmacokinetics and pharmacodynamics of warfarin, respectively. Purpose of our study was to assess the utility of pretesting patients for the above mutations in predicting tendency for bleeding and achieving target INR. MethodsThis was an audit of data collected between July 2011 and December 2016. For safety and efficacy, patients were divided into two subgroups: those with or without bleeding and those who achieved target INR or not. Chi square test was applied to compare the between group differences and crude Odds Ratio (cOR) calculated. ResultsAmong 521 patients evaluated, most common indication for warfarin therapy was valvular heart disease (210/521 = 40%); 36% (187/521) had at least one bleeding episode; 56% (269/479) had below target INR. 26% (136/521) had polymorphic alleles of CYP2C9 and 69% (358/521) had the GG haplotype of VKORC1. Polymorphic alleles of CYP2C9 or AG/AA haplotype had twice the odds of bleeding (cOR = 2.14 and 2.44 respectively) relative to those with wild CYP2C9 allele or GG haplotype. Combined CYP2C9 mutant alleles and/or AG/AA haplotypes had thrice the odds of bleeding (cOR = 3.12) relative to those with wild CYP2C9 alleles and GG haplotype. Those with GG haplotype had twice the odds (cOR = 1.81) and those with GG haplotype along with wild CYP2C9 allele had four times the odds (cOR = 4.27) of not achieving the target INR relative to those with other haplotype/alleles. All these associations were statistically significant (p < 0.05). ConclusionsPretesting patients for genetic polymorphisms could aid in individualizing warfarin therapy.

Influence of genetic and non-genetic factors on acenocoumarol maintenance dose requirement in a Tunisian population.

We aimed to study potential variables involved in interindividual variability to acenocoumarol (AC) response in order to establish a pharmacogenetic algorithm (PA) that includes clinical and genetic factors to predict adequate AC dose to stabilize anticoagulation in a cohort of Tunisian patients. Genotyping of the CYP2C9, VKORC1, CYP4F2, and CALU polymorphisms was conducted on 246 patients using PCR-RFLP technique. AC normalized maintenance dose (NMD):((mean maintenance dose/international normalized ratio (INR)) equilibrium) was calculated. The statistical study was carried out with SPSS V20. A significant correlation was found between age, BMI, and daily AC dose (r = - 0.397; p < 0.001 and r = 0.215; p = 0.001, respectively). The carriers of mutated alleles CYP2C9*2or CYP2C9*3 or VKORC1 haplotypes (H1 and H7) were associated with AC hyper-sensibility. After adjustment to potential covariates, these patients presented supra-therapeutic INR during treatment period and needed low AC dose (ORs* = 0.28 [0.06-0.60], p = 0.004; ORs* = 0.12 [0.04-0.05], p < 0.001; ORs* = 0.45 [0.24-0.84], p = 0.01; and ORs* = 0.28 [0.06-0.98], p = 0.049, respectively). However, carriers of VKORC1 haplotypes (H3 and H12) or mutated alleles CYP4F2 (rs2108622) or CALU (rs1043550) tend to resist to treatment, hence long period of therapy initiation, and must be treated with high AC dose (ORs* = 2.67 [81.12-5.91], p = 0.013; ORs* = 8.76 [1.07-76.26], p = 0.019; ORs* = 3.12 [1.01-9.63], p = 0.047; and ORs* = 3.96 [1.41-11.09], p = 0.009, respectively). A final multivariate regression model explained 48.1% of the global interindividual variability in AC dose requirement. The PA demonstrated that VKORC1 and CYP2C9 polymorphisms contribution was more important than clinical factors. Applying the PA would allow dose adjustment to treat patients in a personalized manner.

Genetic polymorphism of CYP2C9 and VKORC1 in the Nigerian population: significance for warfarin therapy in the population

Genetic polymorphism of CYP2C9 and VKORC1 in the Nigerian population: significance for warfarin therapy in the population

To study role of clinical variables and VKORC1 polymorphism in determination of stability of INR in neurological patients on acenocoumarol

To study role of clinical variables and VKORC1 polymorphism in determination of stability of INR in neurological patients on acenocoumarol

Genotype distributions of CYP2C9 and VKORC1 in southern Thais and their association with warfarin maintenance dose in patients with cardiac surgery

Background: Pharmacodynamics of warfarin are influenced by genetic polymorphisms of its metabolic enzymes. Objectives: To determine CYP2C9 and VKORC1 genotypes in a population in southern Thailand, and their association with warfarin maintenance doses. Methods: We genotyped CYP2C9*2 (rs1799853), CYP2C9*3 (rs1057910), VKORC1 (rs9923231 and rs9934438) from the blood DNA of 210 healthy controls, and determined the association of 2 polymorphic markers (CYP2C9*3 and rs9923231) in 154 patients with aortic valve protheses, with warfarin maintenance dose and coagulopathy. Results: CYP2C9*3 was detected in 17/210 controls; all were heterozygous variants (-*1*3). No CYP2C9*2 polymorphisms were detected. The 2 VKORC1 polymorphisms were in complete linkage disequilibrium. The genotype distribution of VKORC1 (rs9923231) was 118:72:20 for AA:AG:GG. The warfarin maintenance dose in patients with CYP2C9*1*3 (20.7 mg/week) was significantly less than in patients with CYP2C9*1*1 (31.7 mg/ week; P (AA:AG:GG; 23.8:35.3:47.3 mg/week). The incidence of prolonged prothrombin time (INR > 5) was significantly higher in the VKORC1-AA group (45/76) than the AG (22/64) or GG (3/16) groups. The median time to achieve a stable INR was highest for patients with a GG genotype (342 days) compared with 20 days for those with AA, and 160 days for those with AG. Other factors associated with warfarin maintenance dose were body surface area, age (>45 years), and concomitant drug use. Conclusion: Polymorphisms of CYP2C9*3 and VKORC1 are present in southern Thais. We recommend pharmacogenetic studies of these markers as a component of warfarin therapy. Keywords: Pharmacogenetics, Thai patients, warfarin

ビタミンKエポキシド還元酵素の遺伝子多型 : ワルファリン感受性および血管疾患との関連( 「ビタミンと遺伝子多型」-ビタミンK-)

ビタミンKエポキシド還元酵素の遺伝子多型 : ワルファリン感受性および血管疾患との関連( 「ビタミンと遺伝子多型」-ビタミンK-)

Association of Warfarin Therapy with APOE and VKORC1 Genes Polymorphism in Iranian Population.

Warfarin is a vitamin K antagonist that genetic and non-genetic factors affected on its dose requirement in the patients with cardio vascular disease. The aim of this study was whether the APOE and VKORC1 polymorphisms influence on warfarin dose requirements in the part of Iranian patients. Blood samples were collected from 86 warfarin-treated patients. After extraction of genomic DNA, the VKORC1 (rs9923231) and the APOE (rs429358 and rs7412) polymorphisms were genotyped by PCR-RFLP technique. We found that the Iranian patients carrying genotypes GA or AA of VKORC1 polymorphism tended to receive lower dose of warfarin (p = 0.018). Furthermore, the E3/E3 genotype was observed with the frequency more than 60% in the patients with low dose of warfarin. The BMI and weight also showed a positive correlation with warfarin dose. However, it was not statistically significant (p > 0.05). The results of this study may be useful in defining of warfarin dose algorithms for Iranian patients.

The Impact of Gene Polymorphisms on Anticoagulation Control With Warfarin.

Differences in warfarin maintenance dosages based on the presence of polymorphisms in VKORC1, CYP2C9, CYP4F2, and ORM1 can be determined through dosage adjustment according to routine guidelines. Little is known about whether routine therapy could provide consensus anticoagulation control for patients with different genotypes. This study was carried out to compare anticoagulant control in patients with different genotypes. Six hundred seventy patients using warfarin according to Chinese guidelines were enrolled. Warfarin dosages and monitored international normalized ratios (INRs) were recorded. Genotypes of VKORC1 rs9923231, CYP4F2 rs2108622, CYP2C9 rs1057910, and ORM1 rs17650 polymorphisms were determined. Warfarin dosages and INR were compared between genotypes. Patients with the AGCC*F*F*1*1 polymorphism took longer than patients with the AACC*F*F*1*1 polymorphism (20 vs 5 days, P < .001) to achieve the targeted INR range. The INR values of patients with AACC*F*F*1*3 were unstable and did not enter the stable state control phase until after 35 days. The peak INR of patients with the AACC*F*F*1*3 polymorphism was exceedingly high, with some values exceeding the control range limit of 3.0. Patients with the AACC*F*S*1*1 or AACT*F*F*1*1 polymorphisms exhibited similar INR values as the patients with the AACC*F*F*1*1 polymorphism. This study found that routine medication with warfarin provides significantly different levels of anticoagulant control between patients with wild-type genotypes and patients with heterozygous polymorphism genotypes of VKORC1 rs9923231 or CYP2C9 rs1057910. Patients with heterozygous polymorphism genotypes of VKORC1 or CYP2C9 require genotype-directed therapy with warfarin to increase efficacy and safety in anticoagulant treatment.

Genetic and Non-Genetic Factors Affecting the Quality of Anticoagulation Control and Vascular Events in Atrial Fibrillation

Warfarin has a narrow therapeutic window. We hypothesized that genetic factors related to warfarin metabolism (CYP2C9) and activity (VKORC1) would show stronger associations than modifiable factors with the quality of anticoagulation control and risks for thromboembolism and hemorrhage. In this retrospective cohort analysis, clinical and genetic data were collected from 380 patients with atrial fibrillation (AF) who were followed for an average observation period of 4 years. We evaluated the factors associated with time in therapeutic range (TTR, international normalized ratio [INR]: 2-3) and vascular events (either thromboembolic or hemorrhagic), including both genetic (CYP2C9 and VKORC1 genotype) and modifiable factors (anticoagulation service and warfarin dose assessment interval). The genotypic frequency of CYP2C9*3 (rs1057910) was 9.5% and that of VKORC1 1173C>T (rs9934438) was 16.3%. TTR showed dependence on VKORC1 polymorphism: TTR was higher in carriers of the VKORC1 1173C>T than of the VKORC1 TT genotype (61.7 ± 16.0% versus 56.7 ± 17.4%, P = .031). Multivariate testing showed that the VKORC1 genotype and anticoagulation service were independently related to labile INRs (TTR <65%). Vascular events were observed in 66 patients (18.4%) during the study period. A Cox proportional hazard model showed that the use of anticoagulation service and patients' characteristics, such as AF-thromboembolic risk (CHA2DS2-VASc score: Congestive heart failure, Hypertension, Age 75 years or older, Diabetes mellitus, previous Stroke or transient ischemic attack, Vascular disease, Age 65 to 74 years, female) and consequence (neurologic disability), but not genetic factors, were independently associated with vascular events. Both genetic factor (VKORC1 genotype) and clinical efforts (anticoagulation service) influenced the quality of anticoagulation control. However, clinical events were more strongly associated with patient characteristics and clinical efforts than with genetic factors.

Assessing the relative potency of (S)- and (R)-warfarin with a new PK-PD model, in relation to VKORC1 genotypes.

The purpose of this study is to develop a new pharmacokinetic-pharmacodynamic (PK-PD) model to characterise the contribution of (S)- and (R)-warfarin to the anticoagulant effect on patients in treatment with rac-warfarin. Fifty-seven patients starting warfarin (W) therapy were studied, from the first dose and during chronic treatment at INR stabilization. Plasma concentrations of (S)- and (R)-W and INRs were measured 12, 36 and 60h after the first dose and at steady state 12-14h after dosing. Patients were also genotyped for the G>A VKORC1 polymorphism. The PK-PD model assumed a linear relationship between W enantiomer concentration and INR and included a scaling factor k to account for a different potency of (R)-W. Two parallel compartment chains with different transit times (MTT1 and MTT2) were used to model the delay in the W effect. PD parameters were estimated with the maximum likelihood approach. The model satisfactorily described the mean time-course of INR, both after the initial dose and during long-term treatment. (R)-W contributed to the rac-W anticoagulant effect with a potency of about 27% that of (S)-W. This effect was independent of VKORC1 genotype. As expected, the slope of the PK/PD linear correlation increased stepwise from GG to GA and from GA to AA VKORC1 genotype (0.71, 0.90 and 1.49, respectively). Our PK-PD linear model can quantify the partial pharmacodynamic activity of (R)-W in patients contemporaneously exposed to therapeutic (S)-W plasma levels. This concept may be useful in improving the performance of future algorithms aiming at identifying the most appropriate W maintenance dose.

Dietary and genetic influences on hemostasis in a Yup'ik Alaska Native population.

Fish and marine animals are important components of the subsistence diet of Alaska Native people, resulting in a high ω3 PUFA intake. The historical record for circumpolar populations highlights a tendency for facile bleeding, possibly related to ω3 PUFA effects on platelet activation and/or vitamin K-dependent clotting factors. To evaluate these two scenarios in Yup’ik people of southwestern Alaska, we examined the association between dietary ω3 PUFA intake and activities of clotting factor II, V, fibrinogen, PT, INR, PTT, and sP-selectin in 733 study participants, using the nitrogen isotope ratio of red blood cells as a biomarker of ω3 PUFA consumption. sP-selectin alone correlated strongly and inversely with ω3 PUFA consumption. Approximately 36% of study participants exhibited PIVKA-II values above the threshold of 2 ng/ml, indicative of low vitamin K status. To assess genetic influences on vitamin K status, study participants were genotyped for common vitamin K cycle polymorphisms in VKORC1, GGCX and CYP4F2. Only CYP4F2*3 associated significantly with vitamin K status, for both acute (plasma vitamin K) and long-term (PIVKA-II) measures. These findings suggest: (i) a primary association of ω3 PUFAs on platelet activation, as opposed to vitamin K-dependent clotting factor activity, (ii) that reduced CYP4F2 enzyme activity associates with vitamin K status. We conclude that high ω3 PUFA intake promotes an anti-platelet effect and speculate that the high frequency of the CYP4F2*3 allele in Yup’ik people (~45%) evolved in response to a need to conserve body stores of vitamin K due to environmental limitations on its availability.

Integrated analysis of genetic variation and gene expression reveals novel variant for increased warfarin dose requirement in African Americans

Background Warfarin is commonly used to control and prevent thromboembolic disorders. However, because of warfarin's complex dose-requirement relationship, safe and effective use is challenging. Pharmacogenomics-guided warfarin dosing algorithms that include the well-established VKORC1 and CYP2C9 polymorphisms explain only a small proportion of inter-individual variability in African Americans (AAs). Objectives We aimed to assess whether transcriptomic analyses could be used to identify regulatory variants associated with warfarin dose response in AAs. Patients/Methods We identified a total of 56 expression quantitative trait loci (eQTLs) for CYP2C9, VKORC1 and CALU derived from human livers and evaluated their association with warfarin dose response in two independent AA warfarin patient cohorts. Results We found that rs4889606, a strong cis-eQTL for VKORC1 (log10 Bayes Factor = 12.02), is significantly associated with increased warfarin daily dose requirement (β = 1.1; 95% confidence interval [CI] 0.46 to 1.8) in the discovery cohort (n = 305) and in the replication cohort (β = 1.04; 95% CI 0.33 -1.7; n = 141) after conditioning on relevant covariates and the VKORC1 -1639G>A (rs9923231) variant. Inclusion of rs4889606 genotypes, along with CYP2C9 alleles, rs9923231 genotypes and clinical variables, explained 31% of the inter-patient variability in warfarin dose requirement. We demonstrate different linkage disequilibrium patterns in the region encompassing rs4889606 and rs9923231 between AAs and European Americans, which may explain the increased dose requirement found in AAs. Conclusion Our approach of interrogating eQTLs identified in liver has revealed a novel predictor of warfarin dose response in AAs. Our work highlights the utility of leveraging information from regulatory variants mapped in the liver to uncover novel variants associated with drug response and the importance of population-specific research.

Polymorphisms of VKORC1 and CYP2C9 are associated with warfarin sensitivity in Chinese population

ObjectiveWarfarin is a commonly prescribed anticoagulant for prevention of thromboembolic events. Wide inter-individual dose variation, narrow therapeutic range and risk of serious bleeding result in difficulties in achieving the therapeutic effect. The present study was designed to clarify the real biological significance of the polymorphisms of VKORC1 and cytochrome P450 2C9 (CYP2C9) in warfarin metabolism.MethodsA total of 214 patients with warfarin anticoagulant therapy were selected. During follow-up of anticoagulation, warfarin dosage and associated international normalized ratio values were recorded. Genetic polymorphisms of VKORC1 promoter and from exon 1 to exon 3 and CYP2C9 exon 4 sequence were detected by polymerase chain reaction and gene sequencing.ResultsFive polymorphisms were identified in this research, which were VKORC1 1173C>T (intron 1), 1542G>C (intron 2), 2255C>T (intron 2), 3730C>T (3′-downstream) and CYP2C9 exon 4 −65G>C. VKORC1 1173CT, 1542GC, 2255CT and 3730CT polymorphisms were detected in same patients, but CYP2C9 exon 4 −65GC carriers were different from them. VKORC1 1173CT, 1542GC, 2255CT, 3730CT carriers and CYP2C9 exon 4 −65GC carriers had significantly higher warfarin daily dosage than others (3.2±0.6 vs 3.1±1.1 vs 2.6±0.8 mg/day). Logistic regression analysis revealed VKORC1 1173CT, 1542GC, 2255CT, 3730CT carrier status (odds ratio [OR] =3.233, 95% confidence interval [CI]: 1.259–8.303, P=0.015) and obesity with body mass index >27 kg/m2 (OR =1.223, 95% CI: 1.097–1.363, P<0.001) to have independent and statistically significant contributions to high warfarin dosage.ConclusionIn general, in VKORC1 1173CT, 1542GC, 2255CT and 3730CT carriers and in obese patients, warfarin maintenance doses were significantly higher than in the others.

Influence of NR3C1 and VDR polymorphisms on stable warfarin dose in patients with mechanical cardiac valves

ObjectivesThe aim of this study was to evaluate the associations between polymorphisms of VKORC1, CYP2C9, CYP4F2, NR3C1 and VDR genes and stable warfarin doses in Korean patients with mechanical heart valves. MethodsSeventeen single-nucleotide polymorphisms (SNPs) in 204 patients with stable warfarin dose were analyzed: VKORC1 (rs9934438), CYP2C9 (rs1057910), CYP4F2 (rs2108622), NR3C1 (rs41423247, rs1800445, rs56149945, rs10052957, rs6198, rs33388, rs6196, and rs244465), and VDR (rs1544410, rs11568820, rs731236, rs757343, rs7975232, and rs2228570). Statistical analyses were conducted to evaluate the associations of gene variations with stable warfarin dose. Number needed to genotype was obtained by calculating the percentage of patients whose predicted dose was at least 20% higher or lower than the actual stable dose. ResultsThe combined genotypes of rs7975232 and rs2228570 of the VDR gene revealed a significant association with stable warfarin dose, along with VKORC1, CYP2C9, and CYP4F2 polymorphisms. Patients with the genotype combination GT,TT/CT,CC of VDR rs7975232/rs2228570 required significantly higher stable warfarin dose (5.79±2.02mg) than those with the other genotypic combinations (5.19±1.78mg, p=0.034). Multivariate analysis showed that VDR rs7975232/rs2228570 explained 2.0% of the 47.5% variability in overall warfarin dose. Adding VDR SNP combinations to the base model including non-genetic variables (age, sex, and body weight) and genetic variables (VKORC1 rs9934438, CYP2C9 rs1057910, and CYP4F2 rs2108622) gave a number needed to genotype of 41. ConclusionsThis study showed that stable warfarin dose is associated with VDR SNPs along with VKORC1, CYP2C9, and CYP4F2 SNPs.

Pharmacogenetics-based warfarin dose prediction algorithm for patients with heart valve replacement in Southeast China

This study was designed to analyze the influence of polymorphisms in CYP2C9, VKORC1, CYP4F2, GGCX, and EPHX1 genes on the optimal warfarin dosage in patients who have undergone artificial heart valve replacement and establish an algorithm for use by physicians in Southeast China to predict each patient’s optimal steady-state warfarin dose. One-hundred and ninety-six patients scheduled for heart valve replacement in Southeast China were enrolled in this study. Five genotypes, CYP2C9, VKORC1, CYP4F2, GGCX and EPHX1, were detected using time-of-flight mass spectrometry. Correlations of clinical and genetic factors with optimal steady-state dose of warfarin were analyzed. There were significant correlations between the genotypes of CY2C9, VKORC1, CYP4F2 and the warfarin dosage (P = 0.000, 0.000 and 0.015). Multiple stepwise regression analysis was performed to obtain the following algorithm: [Dose (mg/day) = EXP(0.540 + 0.544 × VKORC1 - 0.392 × CYP2C9 + 0.342 × CYP4F2 + 0.474 × BSA - 0.005 × Age)]. This algorithm could predict 49.2% of the observed differences in optimal warfarin dosage among the enrolled patients. A retrospective validation study comparing this algorithm with the published algorithms used in patient populations of other races revealed that the obtained algorithm had the best accuracy (The smallest MRE: 21.11 ± 19.08 mg/day) and applicability (the largest RE proportion of patients in ideal rang: 58.3%). This study 1) defined the relative contributions of age, body surface area, and polymorphisms in CYP2C9, VKORC1, and CYP4F2 to the optimal steady-state dosage of warfarin; 2) established a dose prediction algorithm for populations in this region that takes into account the clinical, pharmacological and genetic polymorphism data; and 3) clarified the advantages of this algorithm over the established prediction equations. Our algorithm can assist clinicians in Southeast China in prescribing appropriate anticoagulation therapy.

Genotyping of CYP2C9 and VKORC1 polymorphisms predicts south Indian patients with deep vein thrombosis as fast metabolizers of warfarin/acenocoumarin.

Deep vein thrombosis (DVT) is a life-threatening disease. Warfarin and acenocoumarol are anticoagulants used to treat DVT and vary among individuals in terms of treatment response/toxicity. Single nucleotide polymorphisms (SNPs) in CYP2C9 and VKORC1 play a role in the pharmacokinetics and dynamics of warfarin and acenocoumarol and they determine the efficacy of treatment by controlling drug clearance in treated individuals. The aim of the current study was to genotype the critical SNPs of CYP2C9 and VKORC1 genes in a south Indian population in order to understand the metabolizer phenotype of patients with DVT. CYP2C9 (rs1799853, rs1057910, rs1057909, rs28371686) and VKORC1 (rs9923231) SNPs were genotyped in 124 cases of DVT. Genomic regions of these SNPs from genomic DNA were amplified with PCR and directly sequenced using Sanger sequencing except for the SNP rs1799853, which was detected using Sau96I restriction endonuclease-based digestion of variant alleles. Among south Indian patients with DVT, 6.5% (8/124) had the rs1799853 SNP of CYP2C9 and 11% (14/124) had the rs1057910 SNP while 16% (20/124) had the rs9923231 SNP of VKORC1 which were associated with the response to warfarin treatment. None of the patients tested positive for poor drug metabolizing genotypes of the CYP2C9 gene and only 1.6% of the south Indian population was sensitive to warfarin treatment. Genotyping results suggest that a relatively greater amount of the therapeutic drug is required to achieve/maintain the international normalized ratio (INR) in south Indian patients with DVT.

The VKORC1 and CYP2C9 genotypes significantly effect Vitamin K antagonist dosing only in patients over the age of 20 years

Given the qualitative differences in the role of VKORC1 and CYP2C9 polymorphisms in Vitamin K antagonists (VKA) dosing variation between adults and children, we were interested in determining at what age these polymorphism begin to play a more significant role. A prospective cohort study of 190 patients aged 1-86years receiving VKA for treatment of venous thromboembolism. Blood samples were collected beyond the acute thrombotic event when patients were on stable targeted INR (2-3) for plasma testing and VKORC1/CYP2C9 genotyping. Patient demographics including VKA dose were collected. Simple and multiple linear regression was used to assess the relationship of VKA dose with polymorphisms and weight, adjusted for quality of anticoagulation (INR, D-Dimer), liver (AST, ALT) and renal function. In subjects 1-19years of age, weight explained 39.0% of dosing variation with VKORC1 and CYP2C9 playing a minor role. In contrast, in subjects 20-40years weight contributed 23%, VKORC1 44% and CYPC29 49% of the VKA dose variation. Until the age of 19, weight has a far greater effect on VKA dosing variation than VKORC1 and CYP2C9 polymorphisms. During the age of 20-40years, VKORC1 and CYP2C9 play a significant role.

GENETIC POLYMORPHISMS OF CYTOCHROME P450 2C9, VITAMIN K EPOXIDE-REDUCTASE SUBUNIT 1 AND WARFARIN DOSING IN PATIENTS WITH PERMANENT ATRIAL FIBRILLATION

Aim - to assess the influence of genetic polymorphisms of CYP2C9 and VKORC1 on warfarin dosing in patients with permanent form of atrial fibrillation. Methods. The study included examination of 100 patients with coronary heart disease and permanent form of atrial fibrillation; mean age 60.5±5.8 years. Conclusion. In patients with permanent form of atrial fibrillation, genotypes CYP2C9*1/*3, TT and GG genotypes of VKORC1 are associated with low warfarin dose, compared to other genotypes. Genotype CYP2C9*1/*3 increases the risk of bleeding complication during warfarin therapy.

VKORC1 and CYP2C9 polymorphisms related to adverse events in case-control cohort of anticoagulated patients.

Vitamin K antagonists (VKAs) are highly effective but have a narrow therapeutic index and require routine monitoring of the INR. The primary aim of pharmacogenetics (PGx) is to optimize patient care, achieving drug treatments that are personalized according to the genetic profile of each patient. The best-characterized genes involved in VKA PGx involve pharmacokinetics (VKORC1) and pharmacodynamics (CYP2C9) of VKA metabolism. The role of these genes in clinical outcomes (bleeding and thrombosis) during oral anticoagulant (OAC) therapy is controversial. The aim of the present study was to evaluate any potential association between genotype VKORC1 and CYP2C9 and adverse events (hemorrhagic and/or thrombotic), during initiation and long-term VKA treatment, in Caucasian patients. Furthermore, we aimed to determine if the concomitant prescription of other selected drugs affected the association between genotype and adverse events.We performed a retrospective, matched case-control study to determine associations between multiple gene variants, drug intake, and any major adverse effects in anticoagulated patients, monitored in 2 Italian anticoagulation clinics.Our results show that anticoagulated patients have a high risk of adverse events if they are carriers of 1 or more genetic polymorphisms in the VKORC1 (rs9923231) and CYP2C9 (rs1799853 and rs1057910) genes.Information on CYP2C9 and VKORC1 variants may be useful to identify individualized oral anticoagulant treatment for each patient, improve management and quality of VKA anticoagulation control, and monitor drug surveillance in pharmacovigilance programs.