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      Analysis of CYP2C9*2, CYP2C9*3 and VKORC1 -1639 G>A polymorphisms in a population from South-Eastern Europe

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          Abstract

          The CYP2C9 enzyme metabolizes a wide range of relevant drugs, among which are oral anticoagulants. VKORC1 is the pharmacodynamic target of the oral anticoagulants. The genetic polymorphisms CYP2C9*2, CYP2C9*3 and VKORC1 -1639 G>A are the major determinants of the inter-individual variability in the dosage requirements of oral anticoagulants. This study provides a first evaluation of these 3 polymorphisms in a Romanian population. A total of 332 Romanian individuals were genotyped for the CYP2C9*2, CYP2C9*3 and VKORC1 -1639 G>A polymorphisms using the PCR-RFLP technique. Sixty-two individuals (18.7%) were heterozygous for CYP2C9*2, whereas 47 individuals (14.1%) were heterozygous for CYP2C9*3. Fourteen individuals (4.2%) had a CYP2C9*2 homozygous, CYP2C9*3 homozygous or CYP2C9*2/ CYP2C9*3 compound heterozygous genotype. These individuals are predicted to have the lowest CYP2C9 enzymatic activity. The allele frequencies of the CYP2C9*2 and CYP2C9*3 polymorphisms were 11.3% and 9.3% respectively. For the VKORC1 -1639 G>A polymorphism, there were 170 heterozygotes (51.2%) and 55 (16.6%) homozygotes for the A allele. The frequency of the A allele was 42.2%. Overall, the distribution of the CYP2C9*2, CYP2C9*3 and VKORC1 -1639 G>A polymorphisms observed in our cohort is in accordance with other Caucasian populations. A large number of Romanians are expected to harbour at least one CYP2C9 variant allele and/or one VKORC1 -1639 G>A allele. This frequency has major implications in the pharmacogenomics of oral anticoagulants in Romanians.

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          Most cited references 31

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          Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing.

          Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K-epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2-3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer-reviewed gene-drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field.(1).
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            The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen.

            Current dosing algorithms do not account for genetic and environmental factors for warfarin dose determinations. This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements. Studied were 297 patients with stable anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0. Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 (-1639 polymorphism) were performed and venous INR and plasma R- and S-warfarin concentrations determined. The mean warfarin daily dose requirement was highest in CYP2C9 homozygous wild-type patients, compared with those with the variant *2 and *3 alleles (P < .001) and highest in patients with the VKORC1 (position -1639) GG genotype compared with those with the GA genotype and the AA genotype (P < .001). Mean warfarin daily dose requirements fell by 0.5 to 0.7 mg per decade between the ages of 20 to 90 years. Age, height, and CYP2C9 genotype significantly contributed to S-warfarin and total warfarin clearance, whereas only age and body size significantly contributed to R-warfarin clearance. The multivariate regression model including the variables of age, CYP2C9 and VKORC1 genotype, and height produced the best model for estimating warfarin dose (R2 = 55%). Based upon the data, a new warfarin dosing regimen has been developed. The validity of the dosing regimen was confirmed in a second cohort of patients on warfarin therapy.
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              A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin.

              Patients require different warfarin dosages to achieve the target therapeutic anticoagulation. The variability is largely genetically determined, and it can be only partly explained by genetic variability in the cytochrome CYP2C9 locus. In 147 patients followed from the start of anticoagulation with warfarin, we have investigated whether VKORC1 gene mutations have affected doses of drug prescribed to acquire the target anticoagulation intensity. Two synonymous mutations, 129C>T at Cys43 and 3462C>T at Leu120, and 2 missense mutations, Asp38Tyr and Arg151Gln, were identified. None of these mutations was found to affect the interindividual variability of warfarin prescribed. Finally, 2 common polymorphisms were found, 1173C>T in the intron 1 and 3730G>A transition in the 3' untranslated region (UTR). Regardless of the presence of confounding variables, the mean adjusted dose required of warfarin was higher (6.2 mg) among patients with the VKORC1 1173CC genotype than those of patients carrying the CT (4.8 mg; P = .002) or the TT genotype (3.5 mg; P < .001). In the present setting, VKORC1 and CYP2C9 genetic variants investigated accounted for about a third (r2, 0.353) of the interindividual variability. Genetic variants of the VKORC1 gene locus modulate the mean daily dose of drug prescribed to acquire the target anticoagulation intensity.
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                Author and article information

                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                jcmm
                Journal of Cellular and Molecular Medicine
                BlackWell Publishing Ltd (Oxford, UK )
                1582-1838
                1582-4934
                December 2012
                13 December 2012
                : 16
                : 12
                : 2919-2924
                Affiliations
                [a ]Department of Clinical Pharmacology and Toxicology, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, Romania
                [b ]Department of Medical Genetics, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, Romania
                [c ]Department of Clinical Neurosciences, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, Romania
                [d ]Department of Internal Medicine, 5th Medical Clinic, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, Romania
                Author notes
                *Correspondence to: Prof. Dafin F. MUREŞANU, M.D., Ph.D.,, Victor Babes 43, Main Building, Level 1, Cluj-Napoca RO400011, Romania., Tel.: +40724353060, Fax: +40364401482, E-mail: dafinm@ 123456ssnn.ro
                [#]

                These authors contributed equally to this work.

                Article
                10.1111/j.1582-4934.2012.01606.x
                4393720
                22863573
                © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
                Categories
                Original Articles

                Molecular medicine

                oral anticoagulants, romanians, vkorc1, cyp2c9

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