Warfarin dosing: the role of genes

What influence do genes have in warfarin dosing?

One important issue in warfarin therapy is the enormous difference that may exist between patients in the dosing needed to achieve therapeutic levels. A recent study published in PLoS Genetics diggs deep into the basis of the genetic variability in the response to warfarin. They have found that three genes are responsible for this: VKORC1, CYP2C9, CYP4F2.

Takeuchi F, McGinnis R, Bourgeois S, Barnes C, Eriksson N, et al. 2009. A Genome-Wide Association Study Confirms VKORC1, CYP2C9, and CYP4F2 as Principal Genetic Determinants of Warfarin Dose. PLoS Genet 5(3)

Warfarin is widely prescribed to reduce blood clotting in order to protect high-risk patients from stroke, thrombosis, and heart attack. But patients vary widely (20-fold) in the warfarin dose needed for proper blood thinning, which means that initial doses in some patients are too high (risking severe bleeding) or too low (risking serious illness). Our GWAS detected two genes (VKORC1, CYP2C9) already known to cause ~40% of the variability in warfarin dose and discovered a new gene (CYP4F2) contributing 1%–2% of the variability. Since our GWAS searched the entire genome, additional genes having a major influence on warfarin dose might not exist or be found in the near-term. Hence, clinical trials assessing patient benefit from individualized dose forecasting based on a patient’s genetic makeup at VKORC1, CYP2C9 and possibly CYP4F2 could provide state-of-the-art clinical benchmarks for warfarin use during the foreseeable future.

Dr. Dan Jonas, from the UNC School of Medicine, reviewed the role of genetic testing in warfarin therapy. He makes clear that “pharmacogenomics is useful in choosing the initial dosing of warfarin. Subsequent dosage adjustments will still be primarily guided by following INRs”

Pharmacogenomics: Using Genetic Testing to Guide Warfarin Therapy

Download PPT file

Slideshow outline:

  • Genetic Polymorphisms A Key to Human Individuality
  • Single Nucleotide Polymorphisms (SNPs)
  • Single Nucleotide Polymorphisms (SNPs)
  • Individualized Medicine
  • Warfarin is THE example of a narrow therapeutic index
  • Factors that Correlate w/ Warfarin Dose
  • Genes important for Warfarin Pharmacogenetics: CYP2C9, CYP1A1, VKORC1
  • Pharmacogenomics at UNC to Guide Warfarin Therapy
  • When Starting Warfarin… consider Genotype!

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