Genetic and nongenetic factors associated with warfarin doserequirements in Egyptian patients

Shahin, Mohamed H.; Khalifa, Sherief; Gong, Yan; Hammad, Lamiaa N.; Sallam, Mohamed T.H.; Shafey, Mostafa El; Ali, Shawky S.; Mohamed, Mohamed‐Eslam F.; Langaee, Taimour; Johnson, Julie A.

doi:10.1097/fpc.0b013e3283436b86

Cited by 91 publications

(98 citation statements)

References 24 publications

(31 reference statements)

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“…There is conflicting evidence on the association between warfarin doses and dietary factors such as alcohol and tea consumption, smoking and vitamin K intake. High intake of fat-soluble vitamin K theoretically diminishes the effect of warfarin, which interferes with coagulation by inhibiting regeneration of the reduced form of vitamin K. In our study, we did not observe a significant relationship between dietary factors (vitamin K intake, alcohol/tea consumption and smoking) and warfarin maintenance dose contrary to the findings in previous studies [30][31][32]. To investigate the association between dietary factors and warfarin dosage, more controlled studies are needed to achieve reliable results.…”

Section: Discussioncontrasting

confidence: 99%

Impact of Genetic Factors (CYP2C9,VKORC1 and CYP4F2) on Warfarin Dose Requirement in the Turkish Population

Özer

Demırcı

Hızel

et al. 2012

Basic Clin Pharma Tox

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Warfarin has a narrow therapeutic index and displays marked person-to-person variation in dose requirement. Functional polymorphisms at candidate genes can therefore offer utility as biomarkers to individualize warfarin treatment. The main objective of this study was to determine whether and to what extent variability in warfarin dose requirements was determined by polymorphisms in CYP2C9, VKORC1, CYP4F2 (rs2108622) and EPHX1 (rs2292566) in the Turkish population. Patients (n = 107) who had stable doses and international normalized ratio (INRs) at their last three consecutive visits were registered. Their demographic factors, concurrent medications, warfarin-related bleedings or thromboembolisms, smoking, alcohol intake and weekly green vegetable consumption were recorded. From a blood sample, DNA was isolated and genotyped by real-time PCR for polymorphisms of CYP2C9, VKORC1, CYP4F2 and EPHX1. A regression analysis was used to determine the independent effects of genetic and non-genetic factors on warfarin dose optimization. In our study, in addition to age, genetic variants of CYP2C9, VKORC1 and CYP4F2 were found to be significant predictor variables for the maintenance dose for warfarin, explaining 39.3% of dose variability. VKORC1 and CYP2C9 genotypes remain predictor variables of the warfarin dose, and we first found that CYP4F2 (rs2108622) contributes to dose variability in the Turkish population as well. These observations may be of benefit to future translation research with a view to global personalized medicine in regions hitherto understudied such as the Turkish population so as to rationalize initial warfarin dose and reduce the burden of frequent INR measurements.Warfarin is the most commonly used oral anticoagulant for the prevention of stroke in patients with atrial fibrillation, for prophylaxis of venous thromboembolism and pulmonary embolism in patients with prosthetic heart valves and myocardial infarction and for prevention of pulmonary embolism or deep venous thrombosis in patients undergoing orthopaedic surgery or with a history of venous or arterial thromboembolism [1][2][3][4][5]. It is a racemic mixture composed of equal amounts of two enantiomorphs. The levorotatory S-warfarin is four times more potent than the dextrorotatory R-warfarin [6].S-warfarin is primarily metabolized by CYP2C9. The possession of CYP2C9*2 or CYP2C9*3 variant alleles results in decreased enzyme activity and is associated with a significant decrease in the mean warfarin dose because of impaired warfarin metabolism and a higher risk of haemorrhage [7][8][9]. Although CYP2C9 polymorphism affects the mean warfarin dose during warfarin dose adjustment, there are still marked remaining individual differences even in CYP2C9 wild-types in the required dose titration. The target molecule of warfarin, vitamin K epoxide reductase and its gene VKORC1 was sequenced in 2004 [10,11]. Rieder et al. [12] demonstrated that polymorphism in VKORC1 haplotype groups named as A and B explains approximately 25% of the variance...

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Section: Discussioncontrasting

confidence: 99%

Impact of Genetic Factors (CYP2C9,VKORC1 and CYP4F2) on Warfarin Dose Requirement in the Turkish Population

Özer

Demırcı

Hızel

et al. 2012

Basic Clin Pharma Tox

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“…This variability in dose requirement could be attributed to the fact that carriers of the A allele haplotype (i.e., -1639 A) produce less VKORC1 than carriers of B allele haplotype (i.e., -1639 G) [19]. These data are in agreement with those reported by previous studies conducted in Egyptian population [17,18,20].…”

Section: Discussionsupporting

confidence: 90%

Pharmacogenetic Warfarin Dosing Algorithms: Validity in Egyptian Patients

et al. 2018

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Background/Aims: Data from previous reports, addressing the significance of genotype-guided dosing of warfarin in Egyptian patients, are infrequent and controversial. This study is aimed at demonstrating the validity of genetic dosing algorithms in Egyptian patients on warfarin therapy. Methods: A total of 100 Egyptian patients on a stable maintenance daily dose of warfarin were enrolled. The predicted warfarin dose for each patient was calculated using the warfarin dosing table, the Gage and the International Warfarin Pharmacogenetics Consortium (IWPC) clinical algorithms and the Gage and the IWPC genetic algorithms and compared to the actual dose. The accuracy of warfarin dosing algorithms was assessed by using the linear regression analysis. Results: The most accurate model in predicting the ideal dose was the Gage genetic algorithm by R² of 50.4% and the IWPC genetic algorithm by R² of 42.3%, followed by the warfarin dosing table by R² of 19.1%, and the Gage clinical algorithm by R² of 18.9% and the least accurate was the IWPC clinical algorithm by R² of 9.4%. Conclusions: The Gage genetic warfarin dosing algorithm is the best model that could be implemented in Egyptian patients starting warfarin therapy.

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“…The stepwise selection method was used in multiple linear regression to evaluate the contribution of pVNTR-S, CYP2C9*2, and CYP2C9*3, to the warfarin dose requirement, using p Ͻ 0.2 and p Ͻ 0.05 as criteria for entering and staying in the model. Independent studies in whites (Aquilante et al, 2006), African Americans (Gage et al, 2004), Asians (Zhao et al, 2004), and Egyptians (Shahin et al, 2011) have confirmed that both CYP2C9*2 and *3 are functional variants that influence the warfarin dose required to maintain the therapeutic international normalized ratio. Therefore, we performed combined analysis in all the warfarin patients.…”

Section: Cyp2c9 Promoter Pvntr Polymorphism Regulates Gene Expressionmentioning

confidence: 97%

“…To test the clinical effect of the promotervariable number tandem repeat (pVNTR) polymorphism, we assessed the association of the pVNTR genotype with the maintenance warfarin dose required in patients undergoing stable warfarin anticoagulation therapy from the University of Florida (n ϭ 348) (Aquilante et al, 2006) and Cairo, Egypt (n ϭ 207) (Shahin et al, 2011). The relevant protocols were approved by the local institutional review boards.…”

Section: Cyp2c9 Promoter Pvntr Polymorphism Regulates Gene Expressionmentioning

confidence: 99%

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CYP2C9 Promoter Variable Number Tandem Repeat Polymorphism Regulates mRNA Expression in Human Livers

Wang¹,

Sun²,

Gong³

et al. 2012

Drug Metab Dispos

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ABSTRACT:CYP2C9 is involved in metabolism of nearly 25% of clinically used drugs. Coding region polymorphisms CYP2C9*2 and *3 contribute to interperson variability in drug dosage and clinical outcomes, whereas the role of a regulatory polymorphism remains uncertain. Measuring allelic RNA expression in 87 human liver samples, combined with genotyping, sequencing, and reporter gene assays, we identified a promoter variable number tandem repeat polymorphism (pVNTR) that fully accounted for allelic CYP2C9 mRNA expression differences. Present in three different variant forms [short (pVNTR-S), medium (pVNTR-M), and long (pVNTR-L)], only the pVNTR-S allele reduced the CYP2C9 mRNA level compared with the pVNTR-M (reference) allele. pVNTR-S is in linkage disequilibrium with *3, with linkage disequilibrium r 2 of 0.53 to 0.75 in different populations. In patients who were taking a maintenance dose of warfarin, the mean warfarin dose was associated with the copies of pVNTR-S (p ‫؍‬ 0.0001). However, in multivariate regression models that included the CYP2C9*3, pVNTR-S was no longer a significant predictor of the warfarin dose (p ‫؍‬ 0.60). These results indicate that although pVNTR-S reduced CYP2C9 mRNA expression, the in vivo effects of pVNTR-S on warfarin metabolism cannot be separated from the effects of *3. Therefore, it is not necessary to consider pVNTR-S as an additional biomarker for warfarin dosing. Larger clinical studies are needed to define whether the pVNTR-S has a minimal effect in vivo, or whether the effect attributed to *3 is really a combination of effects on expression by the pVNTR-S along with effects on catalytic activity from the nonsynonymous *3 variant.

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Genetic and nongenetic factors associated with warfarin doserequirements in Egyptian patients

Cited by 91 publications

References 24 publications

Impact of Genetic Factors (CYP2C9,VKORC1 and CYP4F2) on Warfarin Dose Requirement in the Turkish Population

Impact of Genetic Factors (CYP2C9,VKORC1 and CYP4F2) on Warfarin Dose Requirement in the Turkish Population

Pharmacogenetic Warfarin Dosing Algorithms: Validity in Egyptian Patients

CYP2C9 Promoter Variable Number Tandem Repeat Polymorphism Regulates mRNA Expression in Human Livers

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