Role of Genetic Variations in the CYP2C9 Gene in Determining the Optimal Dose of Warfarin in a Group of Syrian Patients

2019 ◽  
Vol 12 (2) ◽  
pp. 4505-4511
Author(s):  
Kamar Shayah ◽  
Abduljalil Ghrewati ◽  
Yaser Abajy Mohammad ◽  
Ibrahim Hadid
Keyword(s):  
Frequency Distribution ◽  
Oral Anticoagulant Therapy ◽  
Warfarin Dose ◽  
Optimal Dose ◽  
International Normalized Ratio ◽  
Genetic Variations ◽  
University Hospital ◽  
Dose Requirement ◽  
Cyp2c9 Gene ◽  
Variant Alleles

Genetic variations in drug metabolizing hepatic CYP2C9 gene determine the optimal dose for many drugs including anticoagulants such as warfarin.  Here we sought to detect the frequency distribution of genetic variations of CYP2C9 gene and to determine its potential role in the control of warfarin dose in Syrian patients. The study included 125 patients with high risk of thrombosis of adults who visited the Heart Disease & Surgery Hospital (HDSH) and Aleppo University Hospital (AUH) and treated with warfarin as oral anticoagulant therapy, and the dose-corrected by the international normalized ratio (INR) at least three months ago. Genomic DNA was extracted from blood samples, and genotype analysis for CYP2C9*2 and  CYP2C9*3 variant alleles was done by polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). Data were analyzed using SPSS version 20. The results obtained in this study suggest that Genotype frequency distribution of CYP2C9*2 and CYP2C9*3 variant alleles was found to be different from other populations and has significant effect on warfarin dose requirement (p<0.05). It is concluded that there is a need to include CYP2C9 genetic variations detection tests in the warfarin dosing algorithm, as this has an important role in reducing serious hemorrhagic complications, especially in patients with the CYP2C9*2/*2 and CYP2C9*3/*3 homozygous mutant genotypes. 

scholarly journals Impact of CYP2C9 and VKORC1 Polymorphisms on Warfarin Sensitivity and Responsiveness in Jordanian Cardiovascular Patients during the Initiation Therapy

Genes ◽  
2018 ◽  
Vol 9 (12) ◽  
pp. 578 ◽  
Author(s):  
Laith AL-Eitan ◽  
Ayah Almasri ◽  
Rame Khasawneh
Keyword(s):  
Warfarin Therapy ◽  
Catalytic Properties ◽  
Warfarin Dose ◽  
International Normalized Ratio ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Haplotype Blocks ◽  
Cardiovascular Patients ◽  
Cyp2c9 Gene ◽  
Vkorc1 Gene

Warfarin is an oral anticoagulant frequently used in the treatment of different cardiovascular diseases. Genetic polymorphisms in the CYP2C9 and VKORC1 genes have produced variants with altered catalytic properties. A total of 212 cardiovascular patients were genotyped for 17 Single Nucleotide Polymorphisms (SNPs) within the CYP2C9 and VKORC1 genes. This study confirmed a genetic association of the CYP2C9*3 and VKORC1 rs10871454, rs8050894, rs9934438, and rs17708472 SNPs with warfarin sensitivity. This study also found an association between CYP2C9 and VKORC1 genetic haplotype blocks and warfarin sensitivity. The initial warfarin dose was significantly related to the CYP2C9*3 polymorphism and the four VKORC1 SNPs (p < 0.001). There were significant associations between rs4086116 SNP and TAT haplotype within CYP2C9 gene and rs17708472 SNP and CCGG haplotype within VKORC1 gene and warfarin responsiveness. However, possessing a VKORC1 variant allele was found to affect the international normalized ratio (INR) outcomes during initiation of warfarin therapy. In contrast, there was a loose association between the CYP2C9 variant and INR measurements. These findings can enhance the current understanding of the great variability in response to warfarin treatment in Arabs.

Association between polymorphisms in microRNA seed region and warfarin stable dose

2020 ◽  
pp. postgradmedj-2019-137197
Author(s):  
Maryam Hosseindokht ◽  
Hamed Zare ◽  
Rasoul Salehi ◽  
Leyla Pourgholi ◽  
Shayan Ziaee ◽  
...  
Keyword(s):  
Fragment Length Polymorphism ◽  
Interindividual Variability ◽  
Warfarin Dose ◽  
Optimal Dose ◽  
Seed Region ◽  
Dose Requirement ◽  
Vitamin K Cycle ◽  
Warfarin Dose Requirement ◽  
Potential Factor ◽  
Warfarin Maintenance Dose

BackgroundThe optimal dose of anticoagulant warfarin varies among patients to achieve the target international normalised ratio. Although genetic variations related to warfarin pharmacokinetics and vitamin K cycle are important factors associated with warfarin dose requirements, these variations do not completely explain the large interindividual variability observed in the most populations, suggesting that additional factors may contribute to this variability. microRNAs have recently been introduced as regulators of drug function genes, and therefore, may be involved in drug responses. In this study, we aimed to evaluate the possible association between variants in the seed region of microRNAs, which target the genes involved in the action of warfarin and warfarin dose requirement.Methods526 samples were collected from Iranian patients. Four selected polymorphisms in the seed region of microRNAs (rs2910164, rs66683138, rs12416605 and rs35770269 in miR-146a, miR-3622a, miR-938 and miR-449c, respectively) were genotyped by PCR-restriction fragment length polymorphism method.Resultsrs2910164 C/G in the seed region of miR-146a was associated with warfarin dose requirement (p<0.001); the patients with GG genotype had the higher mean dose of warfarin (40.6 mg/week, compared with 33.9 and 31.8 mg/week for GC and CC genotypes, respectively). The association of other polymorphisms with warfarin dose requirement was not statistically significant.Conclusionrs2910164 C/G in the seed region of miR-146a is associated with warfarin maintenance dose, likely by disrupting interaction between miR-146a and ATP-binding cassette subfamily B member 1 gene, ABCB1. Therefore, this polymorphism may possibly be a potential factor for assessment of warfarin dose requirements.

scholarly journals Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 861-867 ◽  
Author(s):  
Caroline Moreau ◽  
Fanny Bajolle ◽  
Virginie Siguret ◽  
Dominique Lasne ◽  
Jean-Louis Golmard ◽  
...  
Keyword(s):  
Vitamin K ◽  
Dose Response ◽  
Maintenance Dose ◽  
Vitamin K Antagonists ◽  
Warfarin Dose ◽  
International Normalized Ratio ◽  
Individual Variability ◽  
Dose Requirement ◽  
Warfarin Dose Requirement ◽  
Main Determinants

Abstract Managing vitamin K antagonist (VKA) therapy is challenging in children because of a narrow therapeutic range and wide inter- and intra-individual variability in dose response. Only a few small studies have investigated the effect of nongenetic and genetic factors on the dose response to VKAs in children. In a cohort study including 118 children (median age 9 years; range, 3 months-18 years) mostly with cardiac disease, we evaluated by multivariate analysis the relative contribution of nongenetic factors and VKORC1/CYP2C9/CYP4F2 genotypes on warfarin (n = 83) or fluindione (n = 35) maintenance dose and the influence of these factors on the time spent within/above/below the range. The results showed that height, target international normalized ratio and VKORC1 and CYP2C9 genotypes were the main determinants of warfarin dose requirement, accounting for 48.1%, 4.4%, 18.2%, and 2.0% of variability, respectively, and explaining 69.7% of the variability. Our model predicted the warfarin dose within 7 mg/wk in 86.7% of patients. None of the covariates was associated with the time spent above or below the international normalized ratio range. Whether this model predicts accurately the effective maintenance dose is currently being investigated.

Intrahospital Correlation of the International Normalized Ratio

2008 ◽  
Vol 15 (2) ◽  
pp. 220-224 ◽  
Author(s):  
Alejandro Lazo-Langner ◽  
Rosario Villa-Márquez ◽  
Darinel Hernández-Hernández ◽  
Sonia Rojas-Maya ◽  
Josefa Piedras
Keyword(s):  
Oral Anticoagulant Therapy ◽  
Warfarin Dose ◽  
Correlation Coefficients ◽  
Coagulation Factors ◽  
International Normalized Ratio ◽  
Rabbit Brain ◽  
Clinical Use ◽  
Altman Analysis ◽  
Bland Altman Analysis ◽  
Highly Sensitive

Background. Monitoring of oral anticoagulant therapy (OAT) is usually accomplished by measuring prothrombin time and the international normalized ratio (INR). However, thromboplastins have different responsiveness and sensitivity to vitamin K—dependent coagulation factors depletion. Several studies have shown INR variation when low sensitive thromboplastins are used. This study compared INR variability between two laboratories using highly sensitive thromboplastins. Methods. A total of 237 plasmas were tested, half of them from patients under OAT. Samples were tested simultaneously in two laboratories: in laboratory A, a Behring Coagulation Timer instrument and a human recombinant thromboplastin (Innovin, Dade Behring) (ISI 1.01) were used. In laboratory B, a Thrombolyzer Compact (Behnk Elektronik) and a rabbit brain thromboplastin (Simplastin Excel S, Organon Teknika) with an ISI of 1.30 were used. Statistical analysis was carried out according to the method of Bland and Altman. Results. Even though high correlation coefficients were obtained when comparing both laboratories, Bland—Altman analysis showed a variation of INR between laboratories ranging from −0.77 to +1.07. After logarithmic transformation of data, these values yielded a variation of the INR either 25% below or 44% above. Conclusions. These results are clearly inadequate for clinical use because such a variation would most probably induce the clinician to make a change in warfarin dose. Standardization of instruments, reagents, and controls is warranted to decrease this variation.

A Probable Interaction between Warfarin and the Antiretroviral TRIO Study Regimen

2012 ◽  
Vol 46 (11) ◽  
pp. e34-e34 ◽  
Author(s):  
Michelle D Liedtke ◽  
Amulya Vanguri ◽  
R Chris Rathbun
Keyword(s):  
Drug Interaction ◽  
Warfarin Dose ◽  
International Normalized Ratio ◽  
Dose Requirement ◽  
Vein Thrombosis ◽  
Warfarin Dose Requirement ◽  
Recurrent Deep Vein Thrombosis ◽  
The Mean ◽  
Deep Vein ◽  
Probable Interaction

OBJECTIVE: To report a probable drug interaction between the antiretroviral TRIO regimen (ritonavir-boosted darunavir, etravirine, and raltegravir) and warfarin in an HIV-infected patient. CASE SUMMARY: In January 2010, a 50-year-old transgender female with HIV infection and recurrent deep vein thrombosis began treatment with the TRIO study regimen. Treatment had been maintained with warfarin for the past 5 years and emtricitabine monotherapy for the preceding 22 months. Emtricitabine was discontinued when the TRIO regimen was started. The mean weekly warfarin dose while the patient was receiving emtricitabine monotherapy was 13.3 mg (95% CI 12.7 to 13.8), with a mean international normalized ratio (INR) of 2.8 (95% CI 2.5 to 3.1). Following the initiation of the TRIO regimen, the mean weekly warfarin dose was increased to 19.3 mg (95% CI 18.5 to 20.1) and was maintained over the ensuing 71 weeks with a mean INR of 2.6 (95% CI 2.2 to 3.0). DISCUSSION: Information on the effect of newer antiretrovirals on warfarin metabolism, as well as the collective contribution of combination antiretroviral therapy including multiple agents that may alter warfarin metabolism, is limited. We predicted that warfarin dose requirements would change upon initiation of the TRIO regimen. Given the variability in INR that can occur with chronic warfarin treatment, weekly warfarin doses were averaged during emtricitabine monotherapy (90 weeks) and TRIO regimen (71 weeks) periods. Mean weekly warfarin doses increased by 45% (p < 0.001) following initiation of the TRIO regimen. Mean INR results for the 2 time periods were not significantly different, demonstrating that stable anticoagulation was maintained. The Horn drug interaction probability scale score to assess causation indicated a probable interaction. CONCLUSIONS: An increased weekly warfarin dose requirement is predicted when warfarin is used concurrently with the antiretroviral TRIO regimen. Increased INR monitoring is prudent when the combination is administered.

The Influence of Ethnicity on Warfarin Dosage Requirement

2005 ◽  
Vol 39 (6) ◽  
pp. 1008-1012 ◽  
Author(s):  
Mai-Trang N Dang ◽  
Julie Hambleton ◽  
Steven R Kayser
Keyword(s):  
Asian American ◽  
Repeated Measures ◽  
Maintenance Dose ◽  
Demographic Data ◽  
Warfarin Dose ◽  
Optimal Dose ◽  
Warfarin Dosage ◽  
Inclusion Criteria ◽  
Dose Requirement ◽  
Warfarin Dose Requirement

BACKGROUND: The optimal dose of warfarin varies among individuals, and the prediction of a maintenance dose is difficult. Ethnicity has been reported to influence warfarin dosing. OBJECTIVE: To quantitate the influence of ethnicity on warfarin dose requirement. METHODS: We conducted a retrospective cohort study at a university anticoagulation clinic to evaluate the influence of ethnicity on warfarin dose. Inclusion criteria included age ⩾18 years, target international normalized ratio (INR) 2–3, and warfarin management within the clinic for ⩾3 months with a minimum of 5 clinic visits. We collected clinical and demographic data including age, gender, weight, ethnicity, disease states, concomitant medications, indication, weekly warfarin dosage, and INR. To assess potential confounders, multivariate, repeated-measures regression analysis was used to identify and adjust for variables that may influence the maintenance dose of warfarin. RESULTS: Of the 345 patients who met the inclusion criteria, 27% were Asian American, 6% Hispanic, 54% white, and 14% African American. The adjusted mean (95% CI) weekly warfarin doses for patients with an INR goal of 2 to 3 were Asian Americans 24 mg (21 to 27), Hispanics 31 mg (25 to 37), whites 36 mg (34 to 39), and African Americans 43 mg (39 to 47) (p < 0.001). Additional factors found to influence warfarin dose requirement included age, weight, concomitant use of amiodarone, and diagnosis of venous thromboembolism. CONCLUSIONS: Warfarin dose requirements vary across ethnic groups even when adjusted for confounding factors, suggesting that genetic variation contributes to interpatient variability.

The influence of sequence variations in factor VII, γ-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement

2006 ◽  
Vol 95 (05) ◽  
pp. 782-787 ◽  
Author(s):  
Darja Herman ◽  
Polona Peternel ◽  
Mojca Stegnar ◽  
Katja Breskvar ◽  
Vita Dolzan
Keyword(s):  
Warfarin Dose ◽  
Variable Number ◽  
Factor Vii ◽  
Dose Requirement ◽  
Intron 1 ◽  
Sequence Variations ◽  
Cyp2c9 Gene ◽  
Warfarin Dose Requirement ◽  
Stable Maintenance ◽  
Ggcx Gene

SummaryThe degree of interpatient variability in the warfarin dose required to achieve the desired anticoagulant response can only partly be explained by polymorphisms in the CYP2C9 gene, suggesting that additional genetic factors such as polymorphisms in genes involved in blood coagulation may influence warfarin dose requirement. In total, 165 Caucasian outpatients on stable maintenance warfarin treatment previously genotyped for CYP2C9 were analysed for common polymorphisms in FVII, GGCX and VKORC1 genes. The -402G>A polymorphism and a variable number of repeats in intron 7 of FVII gene did not significantly influence warfarin dose.The mean warfarin doses increased with the number of (CAA) repeats in the GGCX gene, but the differences were significant only in the CYP2C9*1/*1 subgroup of patients (p=0.032). Common polymorphism (6484C>T) in intron 1 of the VKORC1 gene led to lower warfarin dose requirement; the means were 5.70 (95% C.I. 4.95 - 6.45), 3.49 (3.07 - 3.90) and 2.11 (1.80 - 2.42) mg/day for 6484 CC, CT and TT genotypes, respectively (p<0.001). In contrast, 9041G>A polymorphism in 3’UTR of theVKORC1 gene led to higher warfarin dose requirement; the means were 3.09 (2.58 - 3.60), 4.26 (3.69 - 4.82) and 5.86 (4.53 - 7.19) mg/day for 9041 GG, GA and AA genotypes, respectively (p<0.001).With a regression model we explained 60.0% of variability in warfarin dose, which was due to gene polymorphisms (CYP2C9,VKORC1), age and body-surfacearea. When aiming for individualised warfarin therapy, at least VKORC1 polymorphisms should be included in predictive genotyping besides CYP2C9.

Effect of Polymorphisms in the Cytochrome P450 CYP2C9 Gene on Warfarin Anticoagulation

2004 ◽  
Vol 128 (12) ◽  
pp. 1360-1363
Author(s):  
Dorothy M. Adcock ◽  
Charles Koftan ◽  
Domnita Crisan ◽  
Frederick L. Kiechle
Keyword(s):  
Warfarin Therapy ◽  
Standard Dose ◽  
Initial Period ◽  
Warfarin Dose ◽  
Interindividual Variation ◽  
Bleeding Complications ◽  
Cyp2c9 Genotype ◽  
Cyp2c9 Gene ◽  
Variant Alleles ◽  
The Relationship

Abstract Context.—Warfarin is a widely used anticoagulant with efficacy in treatment and prevention of thrombosis. Patient management, however, is difficult because of interindividual variation in response to standard doses due to significant differences in metabolic rates. Warfarin metabolism is under genetic control, involving primarily the CYP2C9 gene encoding the enzyme that catalyzes the conversion of warfarin to inactive metabolites. Objective.—Several polymorphisms of CYP2C9 have been reported; the variant alleles *2 and *3 have decreased enzymatic activity. The objective of this case study is to investigate the relationship between CYP2C9 genotype and warfarin anticoagulation. Design.—A case of deep vein thrombosis treated with the standard warfarin dose is investigated for intensity of anticoagulation and CYP2C9 genotype; the case illustrates the relationship between CYP2C9 variant and overanticoagulation with subsequent bleeding complication. Results.—The patient's genotype, CYP2C9*1*3, correlated with an exaggerated anticoagulant response during the initiation of warfarin therapy at standard dose, and a bleeding episode ensued. Based on heterozygosity for the *3 variant allele, it was recommended that the patient be maintained on a low-dose warfarin regimen. Conclusions.—The practical implications of identifying genetic risk factors that lead to overanticoagulation are multiple. Genotype knowledge of the CYP2C9 variant alleles may help the clinician to individualize warfarin therapy with the ultimate goals of shortening the initial period of induction therapy, reaching a stable maintenance dose earlier, and minimizing bleeding complications in patients who are high responders and need lower warfarin doses.

The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2329-2333 ◽  
Author(s):  
Elizabeth A. Sconce ◽  
Tayyaba I. Khan ◽  
Hilary A. Wynne ◽  
Peter Avery ◽  
Louise Monkhouse ◽  
...  
Keyword(s):  
Body Size ◽  
Warfarin Dose ◽  
Patient Characteristics ◽  
International Normalized Ratio ◽  
Dosing Regimen ◽  
Dose Requirement ◽  
Cyp2c9 Genotype ◽  
Daily Dose ◽  
Warfarin Dosing ◽  
The Impact

AbstractCurrent dosing algorithms do not account for genetic and environmental factors for warfarin dose determinations. This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements. Studied were 297 patients with stable anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0. Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 (-1639 polymorphism) were performed and venous INR and plasma R- and S-warfarin concentrations determined. The mean warfarin daily dose requirement was highest in CYP2C9 homozygous wild-type patients, compared with those with the variant *2 and *3 alleles (P &lt; .001) and highest in patients with the VKORC1 (position -1639) GG genotype compared with those with the GA genotype and the AA genotype (P &lt; .001). Mean warfarin daily dose requirements fell by 0.5 to 0.7 mg per decade between the ages of 20 to 90 years. Age, height, and CYP2C9 genotype significantly contributed to S-warfarin and total warfarin clearance, whereas only age and body size significantly contributed to R-warfarin clearance. The multivariate regression model including the variables of age, CYP2C9 and VKORC1 genotype, and height produced the best model for estimating warfarin dose (R2 = 55%). Based upon the data, a new warfarin dosing regimen has been developed. The validity of the dosing regimen was confirmed in a second cohort of patients on warfarin therapy.

scholarly journals Prediction of Warfarin Dose in Pediatric Patients: An Evaluation of the Predictive Performance of Several Models

2016 ◽  
Vol 21 (3) ◽  
pp. 224-232
Author(s):  
Elizabeth Marek ◽  
Jeremiah D. Momper ◽  
Ronald N. Hines ◽  
Cheryl M. Takao ◽  
Joan C. Gill ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Prediction Models ◽  
Validation Cohort ◽  
Warfarin Dose ◽  
Predictive Ability ◽  
Predictive Performance ◽  
Optimal Dose ◽  
International Normalized Ratio ◽  
Multicenter Trial ◽  
Fixed Dose

OBJECTIVES: The objective of this study was to evaluate the performance of pediatric pharmacogenetic-based dose prediction models by using an independent cohort of pediatric patients from a multicenter trial. METHODS: Clinical and genetic data (CYP2C9 [cytochrome P450 2C9] and VKORC1 [vitamin K epoxide reductase]) were collected from pediatric patients aged 3 months to 17 years who were receiving warfarin as part of standard care at 3 separate clinical sites. The accuracy of 8 previously published pediatric pharmacogenetic-based dose models was evaluated in the validation cohort by comparing predicted maintenance doses to actual stable warfarin doses. The predictive ability was assessed by using the proportion of variance (R2), mean prediction error (MPE), and the percentage of predictions that fell within 20% of the actual maintenance dose. RESULTS: Thirty-two children reached a stable international normalized ratio and were included in the validation cohort. The pharmacogenetic-based warfarin dose models showed a proportion of variance ranging from 35% to 78% and an MPE ranging from −2.67 to 0.85 mg/day in the validation cohort. Overall, the model developed by Hamberg et al showed the best performance in the validation cohort (R2 = 78%; MPE = 0.15 mg/day) with 38% of the predictions falling within 20% of observed doses. CONCLUSIONS: Pharmacogenetic-based algorithms provide better predictions than a fixed-dose approach, although an optimal dose algorithm has not yet been developed.

Sign in / Sign up

Export Citation Format

Share Document