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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
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Pharmacogenetic variants influence vitamin K anticoagulant dosing in patients with mechanical prosthetic heart valves

Linda Koshy1, Raghu Vb2, Madhuma M1

  • 1Centre for Advanced Research & Excellence in Heart Failure, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Trivandrum, Kerala, 695011, India.

Pharmacogenomics
|May 24, 2022
PubMed

Insights

Pharmacogenetic screening for Vitamin K antagonist (VKA) dosing is crucial. VKORC1, CYP2C9, and CYP4F2 gene variants significantly impact VKA dose requirements in patients with mechanical heart valves.

Area of Science:

  • Pharmacogenomics
  • Cardiovascular Medicine
  • Clinical Pharmacology

Background:

  • Vitamin K antagonists (VKAs) are essential oral anticoagulants for patients with mechanical prosthetic heart valves.
  • Accurate VKA dosing is critical to prevent thrombotic and bleeding complications.
  • Individual variability in VKA response necessitates personalized dosing strategies.

Purpose of the Study:

  • To evaluate the predictive value of VKORC1, CYP2C9, and CYP4F2 genotypes on VKA dose requirements.
  • To assess the influence of these genetic variants on VKA dose categories and bleeding events.
  • To determine the contribution of these genotypes to VKA dose variability in a South Indian population.

Main Methods:

  • A cohort of 506 South Indian patients with mechanical prosthetic heart valves receiving VKAs (warfarin or acenocoumarol) were genotyped.
  • Regression analysis was employed to assess the discriminatory ability of mutant genotypes.
  • Genotyping focused on specific variants within VKORC1, CYP2C9, and CYP4F2 genes.

Main Results:

  • Mutant genotypes of VKORC1 (rs9923231), CYP2C9 (*3), and CYP4F2 (*3) were found to significantly influence VKA dose requirements.
  • These genetic variants collectively explained 27.47% of the observed variation in VKA dosage.
  • The study identified a significant association between specific genotypes and VKA dose needs.

Conclusions:

  • Pharmacogenetic screening for VKORC1, CYP2C9, and CYP4F2 genotypes is recommended for optimizing initial VKA dosing.
  • Genetic profiling can improve VKA dose prediction and potentially reduce adverse events in South Indian patients.
  • Personalized VKA therapy based on pharmacogenetics holds promise for improved patient outcomes.

Keywords:
acenocoumarolantagonistsanticoagulantgenotypeheart valvepharmacogenomicsregressionvitamin Kwarfarin

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