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Warfarin pharmacogenetics: a controlled dose-response study in healthy subjects
Daniella L Kadian-Dodov1, Sarina A van der Zee, Stuart A Scott
1Vascular Medicine Section, The Zena and Michael A Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Vascular Medicine (London, England)
|September 14, 2013
Summary
Genetic variants in CYP2C9 and VKORC1 significantly impact warfarin dosing. Genotype-guided algorithms may be more effective in healthier individuals by accounting for these genetic factors.
Area of Science:
- Pharmacogenomics
- Clinical Pharmacology
Background:
- Warfarin dosing exhibits significant inter-individual variability.
- Non-genetic factors are known to influence warfarin response, but their contribution relative to genetics is not fully elucidated.
Purpose of the Study:
- To quantify the contribution of genetic variants to warfarin dose variability under controlled conditions.
- To assess the impact of specific gene variants (CYP2C9, VKORC1, CYP4F2) on warfarin dosing requirements.
Main Methods:
- A warfarin dosing algorithm was applied to 30 healthy subjects.
- International Normalized Ratio (INR) was monitored daily until therapeutic levels (≥ 2.0) were achieved.
- Cumulative warfarin dose and time to reach target INR were primary outcome measures.
Main Results:
- Carriers of CYP2C9 and VKORC1 variants required significantly lower cumulative warfarin doses.
- CYP4F2 variant carriers needed higher doses.
- Subjects with combined CYP2C9 and VKORC1 variants reached the target INR in fewer days compared to wild-type or single-variant carriers.
Conclusions:
- Genetic factors account for a substantial portion (~62%) of warfarin dose variability, exceeding previous estimates.
- The influence of genetic variants on warfarin dosing is more pronounced in individuals without confounding clinical variables.
- Genotype-guided warfarin dosing may be particularly reliable in healthier populations.
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