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Novel associations of VKORC1 variants with higher acenocoumarol requirements

Ana Isabel Anton1, Juan J Cerezo-Manchado, Jose Padilla

  • 1Centro Regional de Hemodonación and Morales Meseguer Hospital, University of Murcia, Murcia, Spain.

Plos One
|May 22, 2013
PubMed

Insights

New VKORC1 gene variants were found to be associated with higher acenocoumarol doses in patients undergoing oral anticoagulant therapy. These findings may refine pharmacogenetic algorithms for personalized medicine.

Area of Science:

  • Pharmacogenomics
  • Molecular genetics
  • Cardiovascular medicine

Background:

  • Oral anticoagulant therapy (OAT) management benefits from algorithms integrating clinical and genetic data.
  • VKORC1 and CYP2C9 gene polymorphisms are established determinants of coumarin dose, with no other significant pharmacogenetic variants previously identified.

Purpose of the Study:

  • To discover novel genetic variations within the VKORC1 gene that influence oral anticoagulant therapy.
  • To enhance the precision of pharmacogenetic models for acenocoumarol dosing.

Main Methods:

  • Genotyping of VKORC1 rs9923231 and CYP2C9 polymorphisms in 3949 acenocoumarol users.
  • Sequencing of the VKORC1 gene in 57 patients with unexpected dosing requirements.
  • Multivariate linear regression analysis to assess the impact of identified variants on acenocoumarol dose.

Main Results:

  • Novel VKORC1 variants, including rs17878544, rs55894764, and rs7200749, were identified in patients requiring higher-than-expected acenocoumarol doses.
  • The D36Y and rs55894764 variants demonstrated a statistically significant, though minor, effect on acenocoumarol dose.
  • The predictive model for acenocoumarol dosing improved slightly from 39% to 40% with the inclusion of these new variants.

Conclusions:

  • The study successfully identified new VKORC1 variants associated with increased acenocoumarol dosage.
  • The identified variants exhibit a low effect size, necessitating further research into their functional impact on VKORC1.
  • Future studies should evaluate the clinical utility and cost-effectiveness of incorporating these variants into pharmacogenetic algorithms for OAT.
Abstract

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