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...

The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the individual patients level to capture the possible effect of ethnicity, gene-gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7-10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived.

This is the first study to demonstrate that pantoprazole has a relaxing effect in isolated LESs. These results might have significant clinical implications for the subset of patients using proton pump inhibitors who do not receive full symptomatic alleviation from gastroesophageal reflux disease.

No abstract

No abstract