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Influence of CYP2C9, VKORC1, and CYP4F2 polymorphisms on the pharmacodynamic parameters of warfarin: a cross-sectional study

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Abstract

Background

Warfarin is the most commonly evaluated drug in pharmacogenetic-guided dosing studies. However, gaps remain regarding the influence of the genetic polymorphisms of CYP2C9, VKORC1, and CYP4F2 on specific pharmacodynamic parameters like the warfarin sensitivity index (WSI), prothrombin time international normalized ratio (PT-INR), and log-INR variability.

Methods

A cross-sectional study was conducted in non-smoking adults receiving warfarin for at least 6 months. Their demographics, diagnoses, warfarin dosing regimen, concomitant drugs, PT-INR, and bleeding episodes were obtained. CYP2C9 (rs1057910-*3 and rs1799853-*2 alleles), CYP4F2 (rs2108622), and VKORC1 (rs9923231) polymorphisms were assessed using real-time polymerase chain reaction. Three genotype groups (I-III) were defined based on the combined genetic polymorphisms of CYP2C9 and VKORC1 from the FDA’s recommendations. Key outcome measures included anticoagulation control, time spent in therapeutic range, stable warfarin dose, WSI, log-INR variability, and Warfarin Composite Measure (WCM).

Results

The study recruited 236 patients; 75 (31.8%) carried a functional CYP2C9 variant allele, and, 143 (60.6%) had at least one T allele in CYP4F2 and 133 (56.4%) had at least one T allele in VKORC1. Groups’ II and III CYP2C9 and VKORC1 genotypes were observed with reduced stable warfarin dose, increased WSI, higher log-INR variability, and increased bleeding risk. The presence of *2 or *3 allele in CYP2C9 was observed with reduced stable warfarin doses akin to the presence of T alleles in VKORC1; however, the doses increased with T alleles in CYP4F2.

Conclusion

The evaluated genetic polymorphisms significantly influenced all the pharmacodynamic parameters of warfarin. Evaluating CYP2C9, VKORC1, and CYP4F2 genetic polymorphisms prior to warfarin initiation is likely to optimize therapeutic response.

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Acknowledgements

We thank the AGU RCSI-MUB steering committee for approving funding for this research proposal. We are grateful to all the staff nurses who assisted us during the study conduct. We also thank Prof. Reginald Sequeira for his initial liaison with the RCSI-MUB collaborators.

Funding

The study was funded by AGU RCSI-MUB Joint research grant with the Grant number 2019-2.

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain

    Kannan Sridharan

  2. Department of Cardiology, Salmaniya Medical Complex, Ministry of Health, Manama, Kingdom of Bahrain

    Rashed Al Banna & Aysha Husain

  3. Department of Medical Biochemistry, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain

    Zainab Malalla & Mai Sater

  4. RCSI-MUB, Manama, Kingdom of Bahrain

    Aysha Husain & Sameer Otoom

  5. Department of Family Medicine, RCSI-MUB, Manama, Kingdom of Bahrain

    Ghufran Jassim

Authors
  1. Kannan Sridharan
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  2. Rashed Al Banna
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  3. Zainab Malalla
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  4. Aysha Husain
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  5. Mai Sater
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  6. Ghufran Jassim
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  7. Sameer Otoom
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Contributions

Conceived the idea and obtained funding: KS; data acquisition and analysis: KS, RA, AH; genotyping: ZM, MS; data interpretation: KS, MS, GJ, SO; drafting the work: KS; critical revision and final approval of the version: KS, RA, ZM, AH, MS, GJ, SO; accountability: KS.

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Correspondence to Kannan Sridharan.

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Sridharan, K., Al Banna, R., Malalla, Z. et al. Influence of CYP2C9, VKORC1, and CYP4F2 polymorphisms on the pharmacodynamic parameters of warfarin: a cross-sectional study. Pharmacol. Rep 73, 1405–1417 (2021). https://doi.org/10.1007/s43440-021-00256-w

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  • DOI: https://doi.org/10.1007/s43440-021-00256-w

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