VKORC1 and CYP2C9 genotypes in Egyptian patients with warfarin resistance

Azzam, Hanan; Elwakeel, Hossam; Awad, Ibrahim; El-Farahaty, Reham M.; El‐Gilany, Abdel‐Hady; El-Sharawy, Solafa

doi:10.1097/mbc.0000000000000168

Cited by 8 publications

(7 citation statements)

References 27 publications

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“…In a preliminary study on 41 Egyptian pediatric patients receiving warfarin maintenance therapy, Kamel El-Din et al (11) found that age is the most significant determinant of the warfarin dose and that the presence of the CYP2C9 and VKORC1 gene polymorphisms does not affect the warfarin dose. In contrast, in a recent study on Egyptian patients, Azzam et al (24) suggested that the VKORC1-1639 GG and wild-type CYP2C9*1*1 genotypes are associated with high dose requirements during warfarin therapy and that VKORC1-1639 GG is responsible for warfarin resistance and failure. We considered CYP2C9 and VKORC1 genetic polymorphisms in addition to age and height, while the ideal dose requirements were calculated.…”

Section: Discussionmentioning

confidence: 88%

“…The FDA recommends that clinicians should consider genetic testing of CYP2C9 and VKORC1 polymorphisms in every patient before adjusting the warfarin dose (20,23). Although there are many studies in the literature on the impact of genetic polymorphisms on warfarin dose requirements in adult populations (14,16,20,22,24,25), there are only a few studies of pediatric populations (11)(12)(13). In children, data about the pharmacogenetics of warfarin are limited and inconsistent.…”

Section: Discussionmentioning

confidence: 99%

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

Taskin¹

2016

Anatol J Cardiol

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The effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirements in a pediatric population Introduction For decades, warfarin has been the most commonly prescribed anticoagulant for the prophylaxis and treatment of venous and arterial thromboembolic disorders. Despite the limitations of warfarin, including a narrow therapeutic range, broad variations in intra-and inter-individual drug requirements, and a relatively high incidence of bleeding complications, its use continues to rise (1-3). The main reasons for its worldwide use are as follows: the drug can be orally administered and its low cost (1-3). The treatment efficacy and safety of the use of warfarin are based on the prothrombin time, which is expressed as the international normalized ratio (INR). The narrow therapeutic range of warfarin means that the effective dose differs among individuals. The latter also has implications in follow-up therapy. Both non-genetic and genetic factors play a role in the metabolism of warfarin. The non-genetic factors involved in the metabolism of the drug are age, race, body mass index (BMI), gender, smoking, concomitant renal or hepatic disease, drug therapy, enteral feeding, impaired absorption or rapid elimination of vitamin K, and dietary vitamin K intake (4-6). Two genes, the cytochrome P450 complex subunit 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1), are mainly responsible for the metabolism of warfarin. CYP2C9, which plays a role in the metabolism of many drugs other than warfarin, is a liver enzyme. The variants of CYP2C9 are CYP2C9*1, CYP2C9*2, and CYP2C9*3. Some studies have shown that the metabolism of warfarin is reduced in patients with the CYP2C9*3 allele and that these patients therefore require a lower dose of the drug (2, 3). Compared to CYP2C9*1, CYP2C9*2 reduces Objective: The aim was to investigate the frequency of genetic polymorphisms of cytochrome P4502C9 (CYP2C9) and vitamin K epoxide reductase complex subunit1 (VKORC1) and determine the effect of these polymorphisms on warfarin dose requirements in pediatric patients. Methods: Fifty-eight pediatric patients with cardiac disease, thrombophilia, or other conditions, taking a stable warfarin dose, aged 0.2-18 years, and with international normalized ratio (INR) between 2 and 3 and 149 healthy children as a control group were included in this prospective, observational study. Patients receiving drugs that interact with warfarin, having chronic liver or renal disease, obesity, or thyroid dysfunctions were excluded. Polymerase chain reaction (real time and restriction fragment length polymorphism) was used to analyze the CYP2C9*2, CYP2C9*3, and VKORC1 polymorphisms. The ideal warfarin dose was calculated according to the patient's age, height, and the presence of CYP2C9*2, CYP2C9*3, and VKORC1 genetic polymorphisms. The mean daily administered doses and ideal doses were compared. Analysis of variance, Student's t-test, logistic regression analysis, and Pearson's correlation analysis were used for statistical ...

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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

Taskin¹

2016

Anatol J Cardiol

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“…Apart from atrial fibrillation (AF), indications studied include stroke, prophylaxis associated with the use of artificial heart valves and continuous‐flow left ventricular assist devices, deep venous thrombosis and pulmonary embolism . Patients studied came from diverse ethnic/racial backgrounds and included not only adult but also paediatric populations …”

Section: Resultsmentioning

confidence: 99%

Genotype‐guided warfarin therapy: Still of only questionable value two decades on

Shah

2020

J Clin Pharm Ther

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What is known and objective: Despite an apparently sound pharmacological basis, clinical studies of genotype-guided warfarin dosing have yielded mixed and conflicting results, leading to reluctance in its clinical implementation. The objective of this critique is to re-evaluate key warfarin pharmacogenetic studies with a view to explaining why this may be so. Methods:Major widely-cited warfarin pharmacogenetic studies as well as recent meta-analyses were identified and a critical analysis of these was undertaken to identify factors that may account for poor clinical implementation of pre-treatment genotyping. Results and discussion: Critical examination of major warfarin pharmacogenetic studies identified a number of methodological concerns such as marked variations in study designs with different variously-defined measures of outcome. Genotype testing involved only a limited number of CYP2C9/VKORC1 alleles. Claims of benefits of genotyping are based almost exclusively on INR-related parameters which are known to be highly time-labile and of limited value in predicting clinical risk orbenefit. This is evidenced by lack of any significant effect of genotyping on rates of bleeding or thromboembolic events. Neither have the effects of potential phenoconversion or medication non-adherence in study populations been adequately investigated. Although the effect of ethnicity/race is now better characterised, studies lack the power to determine whether any benefits claimed are indication-sensitive. What is new and conclusion:Since 60% of inter-individual variability in warfarin dose/ response is due to other factors (many of which are non-genetic), expectations of eliminating this variability simply by CYP2C9/VKORC1 genotyping are over-optimistic and efforts cost-ineffective. Real-world studies have not always corroborated trialsbased claims of clinical benefit. It is time to consider redirecting scarce resources away from the study of warfarin pharmacogenetics to pharmacogenetic research of potentially greater clinical relevance.

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“…The FDA recommends that clinicians should consider genetic testing of CYP2C9 and VKORC1 polymorphisms in every patient before adjusting the warfarin dose ( 20 , 23 ). Although there are many studies in the literature on the impact of genetic polymorphisms on warfarin dose requirements in adult populations ( 14 , 16 , 20 , 22 , 24 , 25 ), there are only a few studies of pediatric populations ( 11 – 13 ). In children, data about the pharmacogenetics of warfarin are limited and inconsistent.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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Objective:The aim was to investigate the frequency of genetic polymorphisms of cytochrome P4502C9 (CYP2C9) and vitamin K epoxide reductase complex subunit1 (VKORC1) and determine the effect of these polymorphisms on warfarin dose requirements in pediatric patients.Methods:Fifty-eight pediatric patients with cardiac disease, thrombophilia, or other conditions, taking a stable warfarin dose, aged 0.2–18 years, and with international normalized ratio (INR) between 2 and 3 and 149 healthy children as a control group were included in this prospective, observational study. Patients receiving drugs that interact with warfarin, having chronic liver or renal disease, obesity, or thyroid dysfunctions were excluded. Polymerase chain reaction (real time and restriction fragment length polymorphism) was used to analyze the CYP2C9*2, CYP2C9*3, and VKORC1 polymorphisms. The ideal warfarin dose was calculated according to the patient’s age, height, and the presence of CYP2C9*2, CYP2C9*3, and VKORC1 genetic polymorphisms. The mean daily administered doses and ideal doses were compared. Analysis of variance, Student’s t-test, logistic regression analysis, and Pearson’s correlation analysis were used for statistical analyses.Results:The frequency of the CYP2C9 and VKORC1 genetic polymorphisms was determined as CYP2C9*1/*1 (54.6%), *1/*2 (16.4%), *1/*3 (24.2%), *2/*3 (2.9%), *3/*3 (1.9%), wild-type VKORC1 (26.6%), heterozygote alleles (52.7%), and mutant alleles (20.8%). Patients with allelic variants were found to require lower warfarin doses, and a 64.5% correlation was found between the calculated ideal doses and the administered warfarin doses.Conclusion:Considering CYP2C9 and VKORC1 genetic polymorphisms prior to commencing warfarin treatment will make it easier to reach target INRs and reduce the rate of complications.

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VKORC1 and CYP2C9 genotypes in Egyptian patients with warfarin resistance

Cited by 8 publications

References 27 publications

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

Genotype‐guided warfarin therapy: Still of only questionable value two decades on

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

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