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Objective:To explore the role of genetic testing of VKORC1 and CYP2C9 in determining the dosage of warfarin after aortic valve replacement.Methods:A total of 172 patients receiving warfarin after aortic valve replacement were divided into a control group(86 cases) and an experimental(86 cases) group based on acceptance of genetic testing. In the experimental group, three loci of VKORC1 and CYP2C9 were tested by polymerase chain reaction-restriction fragment length polymorphism technique, and the initial dose of warfarin was determined based on the genetic testing results and warfarin oral-dose table recommended by U. S. Food and Drug Administration(FDA). In the control group, warfarin(3 mg/d) was used as the initial dose. The international normalized ratio(INR) of each patient was continuously monitored after medication. The percentages of patients meeting the target INR in the two groups at specific time points and at 3-month follow-up after discharge from the hospital were monitored, and the incidence of various adverse events was compared between the groups.Results:Based on the results of genetic testing, 68 patients received 3 mg/d(79.1%), 10 patients received 1.5 mg/d(11.6%), and eight patients received 6 mg/d(9.3%) as the initial dosages of warfarin in the experimental group. The percentages of the patients meeting the target INR on the third and sixth day of postoperative medication were 45.3% and 73.3%, respectively, in the experimental group, and 29.8% and 58.3%, respectively, in the control group( P<0.05). The INR critical values during hospitalization occurred in 2.3% in the experimental group and in 7.1% in the control group, while the percentage of the patients meeting the target INR after 3 months was 86.1% in the experimental group and 83.1% in the control group. Conclusion:Genetic testing may guide the selection of the initial dose of warfarin after heart valve replacement to rapidly achieve a stable dose.
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BACKGROUND: Differences in the performance of suggested warfarin dosing algorithms among different ethnicities and genotypes have been reported; this necessitates the development of an algorithm with enhanced performance for specific population groups. Previous warfarin dosing algorithms underestimated warfarin doses in VKORC1 1173C carriers. We aimed to develop and validate a new warfarin dosing algorithm for Korean patients with VKORC1 1173C.METHODS: A total of 109 patients carrying VKORC1 1173CT (N=105) or 1173CC (N=4) were included in this study. Multiple regression analysis was performed to deduce a new dosing algorithm. Following literature searches for genotype-guided warfarin dosing algorithms, 21 algorithms were selected and evaluated using the correlation coefficient (ρ) of actual dose and estimated dose, mean error, and root mean square error.RESULTS: The developed algorithm is as follows: maintenance dose (mg/week)=exp [3.223−0.009×(age)+0.577×(body surface area [BSA])+0.178×(sex)−0.481×(CYP2C9 genotype)+0.227×(VKORC1 genotype)]. Integrated variables explained 44% of the variance in the maintenance dose. The predicted and actual doses showed moderate correlation (ρ=0.641) with the best performance with a mean error of −1.30 mg/week. The proportion of underestimated groups was 17%, which was lower than with the other algorithms.CONCLUSIONS: This is the first study to develop and validate a warfarin dosing algorithm based on data from VKORC1 1173C carriers; it showed superior predictive performance compared with previously published algorithms.
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Humans , Genotype , Korea , Population Groups , WarfarinABSTRACT
OBJECTIVE: To investigate the genetic variation of warfarin response associated genes cytochrome P450 4F2 (CYP4F2) and vitamin K epoxide reductase complex subunit 1 (VKORC1) in Hui Chinese. METHODS: Genomic DNA was extracted from 159 healthy Hui Chinese volunteers and 13 exons of CYP4F2 and three exons of VKORC1 and the exon-intron junction were amplified by polymerase chain reaction and sequenced subsequently through Sanger′ sequencing method. Functional prediction of the non-synonymous SNPs was performed by PolyPhen-2, SIFT and MutationTaster-2. Linkage disequilibrium (LD) was assessed for each genetic variant using HAPLOVIEW. RESULTS: There were 18 genetic variants (nine in the introns and nine in the exons) identified in CYP4F2 in this study, three of which were novel, ie, -14G>C in intron 1, 5039C>T (p.Ala118Val) in exon 4 and 18227A>C (p.Glu452Ala) in exon 12. Nine single nucleotide polymorphisms (SNPs) were detected in VKORC1, three of which were in the exons. Strong LD was found in the identified variants of CYP4F2 and VKORC1. Variant allele frequencies of CYP4F2 Val433Met (0.370) and VKORC1-1639G>A (0.608) in the Hui Chinese were significantly different from those of world populations in the 1 000 Genomes Project. CONCLUSION: Special population genetic patterns of CYP4F2 and VKORC1 are found in Hui Chinese and these RESULTS: would be useful information for the precise medication in Hui Chinese.
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Objective: To explore the effects of genetic factors and non-genetic factors on warfarin dosage in pregnant women after heart valve replacement. Methods: Totally 68 pregnant women were treated with warfarin throughout pregnancy. PCR-chip method was used to detect the polymorphism of CYP2C9 and VKORC1 gene,and the clinical data were collected. The effects of genetic factors and non-genetic factors on stable dosage of warfarin were statistically analyzed. Results: CYP2C9, VKORCl genotypes and weight had sig-nificant effects on warfarin dosage. The three variables could explain 44. 6% of warfarin individual differences. Conclusion: Genetic factors have significant effect on warfarin dosage in pregnant patients, so the detection of genetic polymorphism of CYP2C9 and VKORCl can be applied to individualize warfarin dosage in pregnant patients with heart valve replacement.
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Objective To establish genotyping methods for vitamin K epoxide reductase complex subunit 1 (VKORC1)and cytochrome P450 2C9(CYP2C9)based on pyrosequencing technique to detection of warfarin metabolizing enzyme related gene polymorphisms.Methods A total of 50 peripheral blood samples from healthy adults were collected and the whole blood genomic DNA was extracted.A set of biotin-labeled amplifi-cation primers and sequencing primers were designed respectively for three SNP sites:VKORC1 -1639 G>A,CYP2C9 430C> T and CYP2C9 1075A>C.After PCR amplification of the samples,pyrophosphoric acid se-quencing was conducted.And then the signal peaks form were combined to analyze and determine each sample genotype.Genotyping results were verified by Sanger sequencing,and the consistency of the two sequencing methods was compared.Results Genotypes of the three SNPs can be clearly determined according to the ba-ses and height of the signal peaks.Among the 50 samples,there were 41 AA and nine AG for VKORC1 -1639G>A,accounting for 82% and 12% respectively,and there were 45 *1/*1,five *1/*3 for CYP2C9, accounting for 90% and 10% respectively,no CYP2C9*2 allele detected.Genotype results detected by pyrose-quencing and Sanger sequencing were consistent with each other.Conclusion In SNP genotyping,Pyrose-quencing has the advantages of convenience,time-saving,cheap with accurate and reliable results,which can quickly determine the genotypes of CYP2C9 and VKORC1.
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Objective To understand the frequency distribution of CYP2C9 and VKORC1 gene single nucleotide polymor-phisms in Yunnan Han population.Methods CYP2C9(430C> T,1075A>C and 1080C> G)locus and VKORC1(-1639G> A and 1173C> T)locus gene polymorphisms in 202 samples were detected by adopting electrochemical gene sensor method,and the allele frequencies and genotype frequencies were performed the statistics and the gene polymorphism in relevant populations was an-alyzed.Results Among 202 samples,202 cases(100.0%)were genotype C/C at CYP2C9 * 2 locus,C allele frequency was 100.0%;185 cases(91.6%)were genotype A/A at CYP2C9*3 locus,15 cases(7.4%)were A/C genotype,2 cases(1.0%)were C/C genotype,A allele frequency was 95.3%,C allele frequency was 4.7%;CYP2C9*5 locus genotype C/C was in 202 cases (100.0%),C allele frequency was 100%;VKORC1 -1639G > A locus genotype A/A was in 145 cases(71.8%),57 cases (28.2%)were G/A genotype,A allele frequency was 85.9%,G was 14.1%;1173C> T locus genotype T/T was in 145 cases (71.8%),C/T gene type in 57 cases(28.2%),T allele frequency was 85.9%,and C was 14.1%.Conclusion The distribution of CYP2C9 gene in Yunnan Han population is similar to that in other regions of our country.The VKORC1 gene is different from the foreign population,Chinese Han nationality and partial minority nationalities.
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Objective To establish a LNA-taqman-based real-time PCR assay for detecting gene polymorphisms of Vitamin K monooxygenase CYP4F2,vitamin K epoxide reductase complex subunit 1(VKORC1)and cytochrome P450 2C9(CYP2C9), associated with Warfarin optimal dosage.Methods A set of allele-specific PCR primers and probes was designed for each single nucleotide polymorphism(SNP)of CYP4F2-1347C>T,CYP2C9*3,VKORC1-1173C>T and VKORC1-1639G>A, and the specificity of LNA-taqman probe PCR was evaluated.Genomic DNA of peripheral blood samples from 150 patients with treated with warfarin was extracted,and the some PCR products were verified with sequencing.Results ①LNA-taq-man-based real-time PCR assay was highly specificity,no overla.②Among the 150 patients,the cases of CC,CT and TT genotype of CYP4F2-1347C>T were 87(58%),56(37.3%)and 7(4.7%).The cases of *1/*1 and *1/*3 genotype of CYP2C9*3 were 142(94.7%)and 8(5.3%),*3/*3 genotype was not detected.The cases of TT,TC and CC genotype of VKORC1 1173C>T were 127(84.7%),20(13.3%)and 3(2%).The cases of AA,AG and GG genotype of VKORC1 1639G>A were 124(82.7%),23(15.3%)and 3(2%),respectively.Conclusion The LNA-taqman-based real-time PCR as-say is convenient,inexpensive,accurate and will be useful for CYP4F2-C1347T,CYP2C9* 3,VKORC1-C1173T and VKORC1-G1639A genotyping in a clinic laboratory.
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Objective To evaluate the effect of gene polymorphisms in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) on warfarin maintenance dose and plasma concentration in Chinese Han population in Shanghai. Methods A total of 226 patients who underwent oral warfarin anticoagulation therapy after valve replacement under cardiopulmonary bypass were enrolled in this study. The CYP2C9 1061A/C and VKORC1 -1639 G/A and 1173C/T genotypes were determined by pyrosequencing. The plasma level of warfarin was determined by the UPLC/MS-MS method. The patients were divided into different groups based on genotypes, sex and age. The average daily dose of warfarin and plasma concentration of warfarin were compared between different groups, and the contributions of genotype, plasma concentration, sex and age to warfarin daily dose were calculated. Results Maintenance dose of warfarin in patients withCYP2C9 1061A/C AA type was significantly higher than those with CYP2C9 1061A/C AC type (P<0.05). Maintenance dose of warfarin in patients with VKORC1 -1639G/A AG type was significantly higher than those with VKORC1 -1639G/A AA type (P<0.01). Maintenance dose of warfarin in patients with VKORC1 1173C/T CT type was significantly higher than those with VKORC1 1173C/T TT type (P<0.01). Significant differences of plasma warfarin concentration were also observed between VKORC1 -1639 G/A AA and AG as well as 1173C/T TT and CT genotypes (P<0.01), but not in those with CYP2C9 1061A/C genotypes. The average daily dose of warfarin was significantly higher in male patients than in females (P<0.05). The maintenance dose of warfarin was also significantly higher in patients under 60 years old than those aged above 60 years (P<0.05). CYP2C9 1061A/C, VKORC1 -1639G/A, and VKORC1 1173C/T gene polymorphisms, plasma concentration, age and gender accounted for 7.2%, 29.1%, 30.4%, 6.7%, 1.6% and 1.4% of warfarin dose variance, respectively; and multi-factor combination accounted for totally 47.2% of warfarin dose variance. Conclusion CYP2C9 1061A/C, VKORC1 -1639 G/A and VKORC1 1173C/T genotypes are associated with lower levels of warfarin dose. VKORC1 -1639G/A and 1173C/T genotypes also have a close relationship with warfarin plasma concentration. Sex and age are the important non-genetic influencing factors on warfarin daily dose.
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Background: The dose of oral anticoagulants (OAC) shows great variability among patients. Pharmacogenetic studies have shown that common variants in genes CYP2C9 (*2 and *3) and VKORC1 (-1639G>A) are associated with lower requirements of OAC. Aim: To study the association between average maintenance doses of oral anticoagulant therapy required to maintain a stable INR and CYP2C9 and VKORC1 gene variants in Chilean adults. Material and Methods: Prospective study of patients on anticoagulant treatment and with a stable international normalized ratio (INR) for prothrombin time for at least three months. Patients were classified as having high or low acenocoumarol or warfarin requirements. Peripheral blood DNA genotyping was performed by polymerase chain reaction and restriction fragment polymorphism or sequencing and electrophoresis. Results: The study included 185 patients, 125 on acenocoumarol and 60 on warfarin. Patients with VKORC1-1639A allele were more likely to require lower doses of both drugs than patients with the G allele (Odds ratio [OR] for acenocoumarol 9.06, and OR for warfarin = 18.7). There was no association between CYP2C9*2 and*3 and acenocoumarol or warfarin requirements. Conclusions: There is an association between VKORC1-1639A variant and anticoagulant doses.
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Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Young Adult , Anticoagulants/administration & dosage , /genetics , Polymorphism, Genetic/genetics , Vitamin K Epoxide Reductases/genetics , Acenocoumarol/administration & dosage , Administration, Oral , Chile , Dose-Response Relationship, Drug , Gene Frequency/genetics , Genetic Variation/genetics , Genotype , International Normalized Ratio , Prospective Studies , Prothrombin Time , Warfarin/administration & dosageABSTRACT
Introduction: Warfarin/Acitrom administration dosage varies based on patient genotype with respect to the gene: Vitamin K epoxide reductase complex 1 (VKORC1). Ethnic diversity contributes to genotype variation. The frequency of polymorphism at VKORC1 in population of Hyderabad has not been reported in literature; hence the present study was conducted. Material & Methods: Genomic DNA from peripheral blood leukocytes of patients on warfarin/acitrom as well as normal control population without any thrombotic disease was extracted and Restriction Fragment Length Polymorphism (RFLP) pattern was established for 1173C>T transition by standard protocols. Result: The incidence of homozygote dominants (CC) genotypes were 74.63% and that of heterozygotes (CT) were 25.37 %. No recessives were found in the study group. Conclusion: Presently genotype based dosage is not implemented. This study through its collaboration with practising cardiologist while establishing the test at our diagnostic centre has also enabled awareness and consequently if followed will improve patient safety.
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OBJECTIVE:To provide basis for the establishment of warfarin individualized administration model that is suitable for Uighurian patients in Xinjiang. METHODS:The genotypes of CYP2C9 and VKORC1 in 200 Uighurian patients in xinjiang were detected and compared with the genotypes and allele frequency of different ethnic populations in world. RESULTS:The frequency of CYP2C9*1/*1 homozygous wild type in Xinjiang Uighurian patients was lower than South Korea,Japan,the United States and Han nationality in China,higher than Turkey;the frequency of *1/*2 heterozygous mutant was lower than Turkey,Sweden and the United Kingdom,higher than South Korea,Japan and Han nationality in China;the frequency of *1/*3 heterozygous mutant was higher than Japan,South Korea,Han nationality in China,the United Kingdom and the United States;the frequency of *3/*3 was higher than the populations above(P<0.05). *1 allele in Xinjiang Uighurian patients was lower than Han nationality in China,Ja-pan,South Korea and the United States,higher than Turkey(P<0.05). *2 allele was higher than Han nationality in China,Japan and South Korea,lower than Turkey,Sweden and the United Kingdom(P<0.05). *3 allele was higher than Han nationality in Chi-na,Japan,South Korea,Sweden,the United Kingdom and the United States(P<0.05). The frequency of VKORC1-1639AA in Xinjiang Uighurian patients was higher than the United States Sweden,the United Kingdom,lower than Singapore,Japan,Taiwan China and Han nationality in China. The frequency of type AG was higher than Singapore,Japan,Taiwan China,Han nationality in China. The frequency of type GG was higher than Singapore,Japan,Taiwan China,Han nationality in China,lower than the United States,Sweden and the United Kingdom(P<0.05). Type A allele in Xinjiang Uighurian patients was lower than Han nation-ality in China,Taiwan China,Japan and Singapore,higher than the United States,Sweden and the United Kingdom;type G was higher than Han nationality in China,Taiwan China,Japan and Singapore,lower than the United States,Sweden and the United Kingdom(P<0.05). CONCLUSIONS:The distribution of CYP2C9 and VKORC1 gene polymorphism in Uighurian patients in Xin-jiang are obviously different from Asian,European and American populations.
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OBJECTIVE: To conduct a retrospective cohort study and determine the influence of the vitamin K epoxide reductase complex subunit 1 (VKORC1) gene alleles on over anticoagulation and bleeding complication in Chinese population. METHODS: Patients who underwent heart valve replacement operation in Cardiovascular Surgery of Fujian Provincial Hospital between January 2011 and August 2013 were included, who took warfarin at least 3 months and whose INR level was controlled between 1.8 and 2.5. Genotypes of VKORC1-1639 G>A were tested by polymerase chain reaction (PCR)-gene sequencing technique. SPSS19.0 software was used to analyze the association between genotypes andwarfarin bleeding complications, adjusted for demographic and clinical factors. RESULTS Totally 196 patients were included, mean age (50.8 ± 10.7) years, 80 males, average follow-up (26.9 ± 11.8) months. Of the 434 patient-year, 18 severe bleeding and 59 minor bleeding occurred in 31patients. Patients with VKORC1-1639 AA were associated with higher bleeding risk than G carriers (HR 3.14; 95% CI: 1.14-8.68). Meanwhile, Kaplan-Meier survival curve showed that time to bleeding evens of VKORC1-1639 AA carriers was shorter than G-carriers(Log-rank test, P=0.03). CONCLUSION: VKORC1-1639 G > A might be the major predictive factor of bleeding complication for warfarin therapy in Chinese patients.
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BACKGROUND AND PURPOSE: Advantages of new oral anticoagulations may be greater in atrial fibrillation (AF) patients of poor anticoagulation control with warfarin. The SAMe-TT2R2 scoring system, based on clinical variables, was recently developed to aid in identifying these patients. In this study, we investigated the association of this clinical composite score with genetic factors related warfarin dosing and the quality of anticoagulation control. METHODS: Clinical and genetic data were collected from 380 consecutive Korean patients with AF (CHA2DS2-VASc score, 3.5+/-1.8) who were followed for an average of 4 years. We evaluated factors associated with time in therapeutic range (TTR, INR 2-3), including the CYP2C9 and VKORC1 genotypes and the SAMe-TT2R2 score (Sex female, Age two co-morbidities], Treatment [interacting drugs, e.g., amiodarone], Tobacco use within 2 years [doubled], and Race non-white [doubled]). RESULTS: The average SAMe-TT2R2 score was 3.4+/-0.9, range 2-7; and 153 patients (40.2%) had SAMe-TT2R2 scores > or =4. Time in specific INR ranges varied depending on the VKORC1 genotype but not with the CYP2C9 genotype or the SAMe-TT2R2 score. TTR was higher in patients with the VKORC1 1173C>T than in VKORC1 TT (61.7+/-16% vs. 56.7+/-17.4%, P=0.031). Multivariate testing showed that VKORC1 genotype but not the SAMe-TT2R2 score was significantly associated with labile INRs. There was no correlation between the SAMe-TT2R2 scores and pharmacogenetic data. CONCLUSIONS: A genetic factor, but none of the common clinical and demographic factors, as combined in the SAMe-TT2R2 score, was associated with the quality of anticoagulation control in Korean patients with AF.
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Female , Humans , Atrial Fibrillation , Racial Groups , Demography , Genotype , International Normalized Ratio , Tobacco Use , WarfarinABSTRACT
Aims: Acenocoumarol, a commonly prescribed oral anticoagulant drug, exhibits wideinter-individual variability in response. This study aimed at evaluating the contribution of genetic variations in Vitamin K epoxide reductase complex, subunit 1 (VKORC1), to variability in the response to acenocoumarol, in patients with cerebral venous thrombosis (CVT). Place and Duration of Study: National Institute of Mental Health and Neuro Sciences, Bangalore, India, between September 2009 and January 2013. Methodology: 476 acenocoumarol-treated aseptic CVT patients (153 males, 323 females) were genotyped for VKORC1 -1639G>A and 1173C>T polymorphisms. Mean daily acenocoumarol dose for achieving and maintaining the optimum international normalized ratio (INR) was calculated for different genotypes. Results: Genotype distribution of VKORC1-1639G>A was as follows: 69.7% were wild,25.6% heterozygous and 4.6%, mutant. Mean acenocoumarol dose required to achieve the optimum INR was lower in heterozygous (1.82±0.71mg/day) and homozygous mutants (1.75±0.69mg/day) when compared to wild type patients (2.31±0.89mg/day). Bearing the VKORC1 -1639A allele independently increased the odds of requiring a low dose (Adjusted OR 3.9; 95% CI 1.97-7.73; p<0.0001). Significant differences in dose requirement during maintenance phase were observed in patients of different genotypes. VKORC1 -1639G>A and 1173C>T were observed to be tightly linked (r2=0.98) and no difference in the genotype distributions was observed between the two polymorphisms. Factors such as age and co-medication with phenytoin were also found to influence the drug dosage. Conclusion: Our findings support the use of VKORC1 genotyping during anticoagulation with acenocoumarol in patients with CVT.
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OBJECTIVE: To analyse the effect of amiodarone on the warfarin anticoagulation effects in different CYP2C9 and VORCORC1 status. METHODS: From January 2010 to November 2012, patients on warfarin therapy with or without amiodarone medication were included whose blood samples were collected and tested in VKORC1 and CYP2C9 genotypes and whose clinical data were collected. The clinical characterics, warfarin medication related data were compared between the groups with and without amiodarone therapy and the genotype status were used in the following subgroup analysis. RESULTS: There are no statistically difference of warfarin dosage or INR(international ratio of PT) value between the groups with and without amiodarone medication and no statistically difference in the following analysis of genotype subgroup. CONCLUSION: The patients on short-duration usage of amiodarone has no obviously effect on warfarin stable dosage and INR value during stable dosage.
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BACKGROUND: Warfarin is a widely used oral agent for anticoagulation therapy. Warfarin has a narrow therapeutic index and a wide variation in the interindividual therapeutic dosage. Recently, genotypes of CYP2C9 and VKORC1 have been found to account for 30-40% of the warfarin dosing variability, and a variety of commercial genotyping assays are being introduced. In this study, we evaluated the Verigene Warfarin Metabolism Nucleic Acid test (Verigene Warfarin assay; Nanosphere, USA) for its accuracy and clinical utility in genotyping CYP2C9*2, CYP2C9*3, and VKORC1 1173C>T. METHODS: We compared the Verigene Warfarin assay with direct sequencing for accuracy in determining the genotypes of CYP2C9*2, CYP2C9*3, and VKORC1 1173C>T using 50 patient samples and 3 commercial DNA samples with known genotypes. The method was also evaluated for turn-around time, hands-on time, and feasibility. RESULTS: The Verigene Warfarin assay demonstrated 100% accuracy for identifying CYP2C9*2, CYP2C9*3, and VKORC1 1173C>T. The turn-around time and hands-on time were 3 hr and 2 min, respectively. The no-call error rate at first attempt was estimated to be 2%. CONCLUSIONS: The Verigene Warfarin assay provides rapid and accurate genotype results. Considering there are only a few steps requiring manual intervention, it would be feasible to implement this assay even in clinical laboratories that lack considerable expertise in molecular diagnostics.
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Humans , DNA , Genotype , Metabolism , Nanospheres , Pathology, Molecular , WarfarinABSTRACT
Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genetic polymorphisms were strongly associated with warfarin dose requirement in Caucasians, African Americans and other populations. Our aim was to evaluate the effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirement in south Indian population. A total of 150 patients on warfarin with stable INR (2- 3.5) for the past 3 months were recruited. The genotypes of CYP2C9*2 and *3 and VKORC1 -1639G>A were compared with mean daily warfarin dose (MDWD). The variant allele frequency of VKORC1 -1639G>A was found to be 10.4% and CYP2C9*2 and CYP2C9*3 were found to be 4.5% and 6.6%, respectively. Our study showed that the mean daily warfarin dose is higher in patients with wild type genotypes of CYP2C9 and VKORC1 compared to those with variant genotypes. Multivariate regression analysis revealed that age, body mass index (BMI), duration of therapy and genetic polymorphisms of CYP2C9 and VKORC1 together contribute to 36.1% variability in MDWD in south Indian population.
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Background & objectives: The effects of vitamin K-dependent proteins in bone mineralization and vascular calcification and the implication of vitamin K epoxide reductase gene (VKORC1) 1173C>T polymorphism in warfarin sensitivity are well known. The main objective of the study was to investigate the relationship between VKORC1 1173C>T polymorphism, bone mineral density (BMD), and atherosclerosis (evaluated by intima-media thickness of the carotid artery and the presence of calcified plaques) in patients suspected to have osteoporosis or osteopenia and referred for BMD determination. Methods: VKORC1 1173C>T polymorphism was evaluated in 239 consecutive patients referred by their physicians for BMD measurement (dual energy X-ray absorptiometry at L2-L4 lumbar spine, femoral neck and total hip). Ultrasonography of the carotid arteries was performed, intima-media thickness (IMT) was measured and the presence of atherosclerotic calcified plaques was recorded. Results: In the patients with osteoporosis and osteopenia there was a higher frequency of TT genotype of VKORC1 1173C>T (P=0.04). The TT genotype was significantly more frequent in the osteoporotic group compared to the osteopenic group (P=0.01). The mean age and body mass index were lower in the patients with normal BMD and TT genotype (P=0.02, P=0.03). There was no correlation between the IMT and VKORC1 1173C>T genotype but the TT genotype had a significant association with the presence of calcified atherosclerotic plaques (P=0.05). This finding was not correlated with normal or pathologic BMD. Interpretation & conclusions: VKORC1 1173C>T polymorphism (TT genotype) was associated with osteoporosis and calcified plaques in the carotid artery in patients referred for BMD measurement. Different mechanisms are probably involved in these associations. TT genotype may serve as a potential genetic marker for the risk of OP and ATS.
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Background & objectives: Studies have demonstrated the effect of CYP2C9 (cytochrome P450) and VKORC1 (vitamin K epoxide reductase complex) gene polymorphisms on the dose of acenocoumarol. The data from India about these gene polymorphisms and their effects on acenocoumarol dose are scarce. The aim of this study was to determine the occurrence of CYP2C9*2,*3 and VKORC 1 -1639G>A gene polymorphisms and to study their effects on the dose of acenocoumarol required to maintain a target International Normalized Ratio (INR) in patients with mechanical heart valve replacement. Methods: Patients from the anticoagulation clinic of a tertiary care hospital in north India were studied. The anticoagulation profile, INR (International Normalized Ratio) values and administered acenocoumarol dose were obtained from the clinical records of patients. Determination of the CYP2C9*2,*3 and VKORC1 -1639G>A genotypes was done by PCR-RFLP (restriction fragment length polymorphism). Results: A total of 111 patients were studied. The genotype frequencies of CYP2C9 *1/*1,*1/*2,*1/*3 were as 0.883, 0.072, 0.036 and that of VKORC1 -1639G>A for GG, AG, and AA genotypes were 0.883, 0.090, and 0.027, respectively. The percentage of patients carrying any of the variant alleles of CYP2C9 and VKORC1 in heterozygous or homozygous form was 34% among those receiving a low dose of ≤20 mg/wk while it was 13.8 per cent in those receiving >20 mg/wk (P=0.014). A tendency of lower dose requirements was seen among carriers of the studied polymorphisms. There was considerable variability in the dose requirements of patients with and without variant alleles. Interpretation & conclusions: The study findings point towards the role of CYP2C9 and VKORC1 gene polymorphisms in determining the inter-individual dose variability of acenocoumarol in the Indian patients with mechanical heart valve replacement.
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Background: The aim of this study is to assess the accuracy of warfarin dosage based on VKORC1 and CYP2C9 genotype in Chinese population. Methods: Blood samples were taken from 37 patients. We compared the warfarin dosage obtained from genotype (according to www.warfarindosing.org) and treatment dosage with international normalized ratio (INR) value within 2.0-3.0. Results: The majority of Chinese people in our study are VKORC1 homozygous AA (89.2%), rarely VKORC1 heterozygous AG and we cannot find a patient with homozygous GG. For CYP2C9 genotype, most patients have the wildtype variants (CYP2C9*2 CC and CYP2C9*3 AA). The warfarin dosage for patients with VKORC1 AA and CYP2C9*3 AC is lower than for patients with other genotype variants. Conclusion: There is no significant difference between pharmacogenetic algorithm (www.warfarindosing.org) and our treatment dosage. Our conclusion is that the pharmacogenetic algorithm is accurate to predict the warfarin dose.