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Polymorphisms of CYP2C9, VKORC1, MDR1, APOE and UGT1A1 Genes and the Therapeutic Warfarin Dose in Brazilian Patients with Thrombosis: A Prospective Cohort Study

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Abstract

Background

There are several pharmacogenetic algorithms to determine the warfarin doses required in patients treated for thromboembolism, but they only explain 60 % of dose variation, suggesting that other genes may influence the dose required.

Objectives

This study aimed to evaluate the impact of clinical factors and CYP2C9*2, CYP2C9*3, VKORC1-1639G>A, MDR1 3435C>T, APOE* ε4, and UGT1A1(TA)n polymorphisms on the warfarin dose required, especially in those individuals requiring a high warfarin dose.

Methods

We studied 116 Brazilian patients who received warfarin therapy for thromboembolism. Associations between dose variability and age, body mass index (BMI), gender, use of warfarin antagonists, and genetic polymorphisms were examined.

Results

CYP2C9*2, CYP2C9*3, VKORC1-1639G>A, and APOE *ε4 were associated with lower warfarin doses. Of these subjects, 21 % required a warfarin dose higher than 70 mg/week, which was associated with a BMI greater than 25 kg/m2, use of warfarin antagonists, and the presence of the MDR1 3435T allele and UGT1A1(TA) 7 polymorphism. These individuals were considered to exhibit warfarin resistance. The individuals with the MDR1 3435TT genotype required a dose 21 % higher than that required by 3435CT and 3435CC individuals. The UGT1A1(TA) 7 allele was positively correlated with the warfarin dose.

Conclusion

CYP2C9*2, CYP2C9*3, VKORC1-1639G>A, and APOE *ε4 were associated with lower warfarin doses, while MDR1 3435C>T and UGT1A1(TA) n polymorphisms were associated with a requirement for higher doses. This is the first study to evaluate warfarin resistance, APOE *ε4 and UGT1A1(TA) n genotypes in the Brazilian population, and the association of these two genotypes with warfarin dose required.

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Acknowledgments

The current study was supported by the Universidade Federal de Minas Gerais and Instituto Hermes Pardini.

Disclosure of Conflicts of interest

V.C. Oliveira Almeida, D.D. Ribeiro, K.B. Gomes, and A.L. Brunialti Godard have no conflicts of interest that are directly related to this study.

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Authors and Affiliations

  1. Department of General Biology, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Cx. Postal 486, Pampulha, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    Vanessa Cristina de Oliveira Almeida, Karina Braga Gomes & Ana Lúcia Brunialti Godard

  2. Department of Molecular Genetics, Hermes Pardini, Minas Gerais, Brazil

    Vanessa Cristina de Oliveira Almeida

  3. Clinical Hospital, Universidade Federal de Minas Gerais, Minas Gerais, Brazil

    Daniel Dias Ribeiro

  4. Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Minas Gerais, Brazil

    Karina Braga Gomes

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  1. Vanessa Cristina de Oliveira Almeida
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Correspondence to Vanessa Cristina de Oliveira Almeida.

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de Oliveira Almeida, V.C., Ribeiro, D.D., Gomes, K.B. et al. Polymorphisms of CYP2C9, VKORC1, MDR1, APOE and UGT1A1 Genes and the Therapeutic Warfarin Dose in Brazilian Patients with Thrombosis: A Prospective Cohort Study. Mol Diagn Ther 18, 675–683 (2014). https://doi.org/10.1007/s40291-014-0121-4

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  • DOI: https://doi.org/10.1007/s40291-014-0121-4

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