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The Influence of CYP2C9 and VKORC1 Gene Polymorphisms on the Response to Warfarin in Egyptians

Indian Journal of Hematology and Blood Transfusion volume 34, pages 328–336 (2018)Cite this article

A Correction to this article was published on 19 March 2018

This article has been updated

Abstract

Warfarin is the most commonly used drug for chronic prevention of thromboembolic events, it also ranks high among drugs that cause serious adverse events. The variability in dose requirements has been attributed to inter-individual differences in medical, personal, and genetic factor. Cytochrome P-450 2C9 is the principle enzyme that terminates the anticoagulant effect of warfarin by catalyzing the conversion of the pharmacologically more potent S-enantiomer to its inactive metabolites. Warfarin exerts its effect by inhibition of vitamin K epoxide reductase. This protein is encoded by vitamin K epoxide reductase complex subunit 1 gene (VKORC1). The current study aimed to investigate the pharmacogenetic effect of CYP2C9 and VKORC1 gene polymorphisms on the patients response to warfarin. One hundred cases starting warfarin treatment and 20 healthy controls were enrolled. The mean daily dose of warfarin was calculated from patient’s medical records. For each patient, less than 10 % variability in warfarin dose and a target international normalized ratio (INR) within the therapeutic target range were required for at least 3 months for one of the following indications (deep vein thrombosis, pulmonary embolism, cerebrovascular stroke and myocardial infarction) prior to inclusion in the study. Tetraprimer amplification refractory mutation system PCR was performed to determine CYP2C9*2, CYP2C9*3, and the VKORC1 1639 G > A genetic polymorphisms. Plasma warfarin determination was performed using rapid fluorometric assay. Plasma warfarin concentration ranged from 2.19 to 10.98 μg/ml with a median 3.52 μg/ml. Supratherpeutic INR was observed in 11 % of the cases. Thromboembolic complications occurred in 7 % of the cases and 8 % of cases experienced major bleeding. High maintenance dose (>7 mg/day) was associated with the combined non VKORC1*2 and homozygous wild type CYP2C9 (CYP2C9*1*1) alleles, while low maintenance dose was associated with the Variant (AG + AA)/Wild (*1/*1). (p value <0.001). CYP2C9 variant was a risk factor for supratherapeutic INR in the multivariate logistic regression model. Thromboembolic complication and incidence of supratherapeutic INR were observed in patients carrying combined VKORC1 Variant (AG + AA) and CYP2C9 Variant (*2/*3). Data from our study suggest that together with clinical factors, VKORC1 and CYP2C9 polymorphisms are important contributors to warfarin dosing and may help predict adverse effects in Egyptian patients.

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Change history

  • 19 March 2018

    The aim of this erratum is to acknowledge that the original version of this article was inadvertently published with incorrect author name and affiliation for a co-author.

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Authors and Affiliations

  1. Hematology Department, Medical Research Institute, Alexandria University, Alexandria, Egypt

    Ahmed M. L. Bedewy

  2. Biotechnology Department, Institute of Graduate Studies and Research, Alexandria University, Alexandria, Egypt

    Salah Showeta & Mostafa Hasan Mostafa

  3. Biochemistry Department, Pharos University in Alexandria, Alexandria, Egypt

    Lamia Saeed Kandil

  4. Abraj Al-Shaker, Zaky Ragab Street, Smouha, Alexandria, 21615, Egypt

    Ahmed M. L. Bedewy

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  1. Ahmed M. L. Bedewy
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  2. Salah Showeta
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  3. Mostafa Hasan Mostafa
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  4. Lamia Saeed Kandil
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Correspondence to Ahmed M. L. Bedewy.

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All procedures performed were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Bedewy, A.M.L., Showeta, S., Mostafa, M.H. et al. The Influence of CYP2C9 and VKORC1 Gene Polymorphisms on the Response to Warfarin in Egyptians. Indian J Hematol Blood Transfus 34, 328–336 (2018). https://doi.org/10.1007/s12288-016-0725-4

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