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

Abstract

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...

International Warfarin Genotype-Guided Dosing Algorithms in the Turkish Population and Their Preventive Effects on Major and Life-Threatening Hemorrhagic Events

“…No deviations from the Hardy-Weinberg equilibrium were observed. The frequencies of VKORC1 and CYP2C9 polymorphisms are within the ranges previously reported for the Turkish population[26], and they are also consistent with the data reported for Middle East and Central Asia populations available in the Human Genome Diversity Project. Significant differences between controlled and uncontrolled patients are present for age, CYP2C9 and INR.…”

“…The Turkish population is a good example of a human group with peculiar genetic features that may affect the accuracy of the international warfarin algorithms. To our knowledge, three previous studies investigated the role of VKORC1 and CYP2C9 genotypes in warfarin dose requirements [24][25][26]. However, these studies developed warfarin algorithms on small samples, and no large warfarin pharmacogenetic studies are available about Middle East populations.…”

“…Although Turkish people share a relevant percentage of their genetic background with Europeans, significant differences are present between Turkish and North European populations, partially explaining the health disparities of Turkish communities in Northern Europe [22,23]. To our knowledge, three previous studies investigated the impact of VKORC1 and CYP2C9 polymorphisms on warfarin dosing in the Turkish populations [24][25][26]. However, no studies investigated the reliability of international algorithms on Turkish patients with no indication of the usefulness of warfarin dosing in Turkey.…”

The Impact of Genetic and Non-Genetic Factors on Warfarin Dose Prediction in MENA Region: A Systematic Review

“…These include variants in the following genes: CYP4F2 , EPHX1 , GGCX1 , MDR1 , factor VII , APOE , CALU and PZ . The MAF for the CYP4F2 (rs2108622) was 40% among Turkish [42], 30% in Omani [40] and 42% in Egyptians [12]. The EPHX1 encodes for a putative subunit of the vitamin K epoxide reductase complex called: microsomal epoxide hydrolase 1 [10].…”

Impact of CYP2C9 and VKORC1 genetic polymorphisms upon warfarin dose requirements in Egyptian patients with acute coronary syndrome

“…This means that sensitivity to the drug is highest for the homozygous genotype in which the lower dose regimens should be applied. Ö zer et al [22] stated that Turkish cardiac patients carrying the wild genotype required a higher dose of warfarin compared with heterozygous and homozygous forms. We found an association between VKORC1 (À1639 G>A) genotypes and the time needed to reach the target INR.…”