The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements in an adult Turkish population

Özer, Nihat; Çam, Neşe; Tangurek, Burak; Özer, Songül Peltek; Uyarel, Hüseyin; Öz, Dilaver; Güney, Mehmet; Çiloğlu, Figen

doi:10.1007/s00380-009-1177-7

Cited by 36 publications

(33 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…16 Most recently, several studies have insisted that VKORC1 and CYP2C9, age, gender and other environmental factors could explain almost one half (45-55%) of the variability in response to warfarin in Caucasian patients. 1,20,21 In Asian patients, the multiple regression model based on the genetic polymorphisms and the nongenetic factors of age and body weight can explain 30-40% of the variance in warfarin dose. 2,4 Cho HJ et al suggested that it explained B32% of the overall variability in warfarin dose requirements given all of the variables studied in Koreans.…”

Section: Discussionmentioning

confidence: 99%

Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients

et al. 2011

View full text Add to dashboard Cite

Warfarin is a commonly prescribed anticoagulant drug for the prevention of thromboembolic disorders. We investigated the contribution of genetic variations of four genes and clinical factors to warfarin dose requirement and provided a warfarin-dosing algorithm based on genetic and clinical variables in Korean patients. We recruited 564 Korean patients on stable anticoagulation. Single nucleotide polymorphisms (SNPs) for the VKORC1, CYP2C9, CYP4F2 and GGCX were analyzed. Using multiple regression analysis, we developed a model to predict the warfarin requirement. The SNPs of VKORC1, CYP2C9, CYP4F2 and GGCX showed significant correlation with warfarin dose. Patients with the 3730AA genotype received significantly higher doses of warfarin than those with the 3730GG (P¼0.0001). For CYP2C9, the highest maintenance dose was observed in the patients with wild-type genotype compared with the variant allele carriers (Po0.0001). The multiple regression model including age, gender, body surface area (BSA), international normalized ratio (INR) and four genetic polymorphisms accounted for 35% of total variations in warfarin dose (R 2 ¼0.3499; Po0.0001). This study shows that age, gender, BSA, INR and VKORC1, CYP2C9 and CYP4F2 polymorphism affect warfarin dose requirements in Koreans. Translation of this knowledge into clinical guidelines for warfarin prescription may contribute to improve the efficacy and safety of warfarin treatment for Korean patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Some of these SNPs are located in cytochrome P450 2C9 (CYP2C9), which is an enzyme that participates in the metabolism of warfarin, and some are in vitamin K epoxide reductase complex 1 (VKORC1), whose inhibition by coumarinbased anticoagulant drugs such as warfarin in turn inhibits the vitamin K-dependent clotting factors. [6][7][8][9][10][11][12] In recent years, Mushiroda, et al reported that the CYP2C9 and VKORC1 haplotype may affect the warfarin maintenance dose. 13) Our group has also shown that there are ethnic differences in terms of the genetic polymorphism of CYP2C9 and VKORC1, 14,15) which suggests that the optimal warfarin dose could vary between ethnicities.…”

mentioning

confidence: 99%

Clinical Significance of Combined CYP2C9 and VKORC1 Genotypes in Japanese Patients Requiring Warfarin

2011

View full text Add to dashboard Cite

SummaryThe individual management of anticoagulation therapy is important for safe medical outcomes, including those of oral surgery. Here, Japanese patients who received warfarin (n = 35) and normal controls (n = 125) were analyzed by real-time PCR to determine the frequencies of single nucleotide polymorphisms in VKORC1 (vitamin K epoxide reductase complex, subunit 1) and CYP2C9 and how these frequencies related to warfarin dose and PT-INR. The genetic polymorphisms CYP2C9 *2 (416 C > T), CYP2C9 *3 (1061 A > C), and intron 1-136 C > T in VKORC1 (1173 C > T) were measured. All patients had the wild-type CYP2C9 gene (*1/*1). All 160 cases had the wild-type (CC) type CYP2C9 *2 , 93.8% had AA type CYP2C9 *3 , 6.2% had AC type CYP2C9 *3 , 1.2% had CC type VKORC1, 13.8% had CT type VKO-RC1, and 85% had TT type VKORC1. The CC type VKORC1 genetic polymorphism was associated with a significantly higher mean warfarin maintenance dose (4.5 ± 0.5 mg) than other VKORC1 genotypes (TT type 2.9 ± 0.1 mg: CT type 3.4 ± 0.3 mg). Categorization of the patients in terms of the combined CYP2C9 and VKORC1 haplotype (the warfarinresponsive index; WRI) revealed the mean daily warfarin maintenance dose was 3.0 ± 0.1 mg for WRI 1 and 3.7 ± 0.3 mg for WRI 2 (P < 0.012). The event survey revealed 2 patients with nonfatal cerebral hemorrhage had a WRI score of 2 (VKORC1 C/T heterozygosity genotype). Thus, CYP2C9 and VKORC1 haplotype analysis allows prediction of warfarin maintenance dosage. The findings may provide a personalized use of warfarin in the field of oral surgery. (Int Heart J 2011; 52: 44-49)

show abstract

“…Rieder et al [12] demonstrated that polymorphism in VKORC1 haplotype groups named as A and B explains approximately 25% of the variance in dose. These two genotypes have also previously been investigated in Turkish patients, and a significant contribution to warfarin dose adjustment was identified [13,14]. After receiving reliable results for CYP2C9 and VKORC1 polymorphism relationship with warfarin dose, several new candidate genes have been investigated [15][16][17].…”

mentioning

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

View full text Add to dashboard Cite

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...

show abstract

The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements in an adult Turkish population

Cited by 36 publications

References 52 publications

Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients

Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients

Clinical Significance of Combined CYP2C9 and VKORC1 Genotypes in Japanese Patients Requiring Warfarin

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

Contact Info

Product

Resources

About