Warfarin is the most widely used anticoagulant in the world and works by antagonizing the effects of vitamin K. It has a very narrow therapeutic range and initiation of dosing produces widely variable responses between individuals. It is therefore difficult to predict the drug dose required to achieve therapeutic International Normalized Ratio (INR) and avoid adverse drug events. Warfarin dosing is typically adjusted to maintain an INR at 2.5 ± 0.5 and at 3.0 ± 0.5 in higher risk patients. Variations of two genes, CYP2D9 and vitamin K epoxide reductase complex 1 gene (VKORC1), account for 30–50% of the variability in response to warfarin. It is therefore thought that analysis of these genes will aid in warfarin dosing recommendations.

Flockhart et al. reported on the findings of a multidisciplinary group of experts in 2006 to evaluate the role CYP2D9 and VKORC1 testing in altering warfarin-related therapeutic goals and reduction of adverse drug events. This review was termed the Rapid-ACCE (Analytical, Clinical Validity, Clinical Utility, and Ethical, Legal and Social Implications) review. The aims were to identify and evaluate the best available evidence for the use of pharmacogenetic testing to guide warfarin use, identify any gaps which were apparent and to offer recommendations on whether the evidence supports the use of testing of CYP2D9 and VKORC1 as a standard of care.

Several genes are involved in the metabolism of warfarin. S-warfarin, the more active isomer, is metabolized predominately by CYP2D9 whose variable metabolism is believed to be responsible for much of the variability in warfarin dose requirements. Deficient CYP2C9 results in decreased metabolism of bioactive S-warfarin and consequently an increased INR at a specified time, above that predicted, based on non-genetic factors alone.

VKORC1 has recently been identified as the major target of warfarin inhibition. VKORC1 converts vitamin K-epoxide, formed during the carboxylation of several proteins, to the vitamin K-quinone, allowing the vitamin K cycle to function catalytically in the generation of γ-carboxyglutamyl residues in proteins, including clotting factors. Relative deficiency of VKORC1 results in less γ-carboxylation of these proteins and the production of clotting factors that are deficient in coagulation activity.

The group looked at various factors including sensitivity and specificity of pharmacogenetic testing and relative risk of adverse events. They concluded that while there is strong evidence to support association between these genetic variants and therapeutic dose of warfarin, this is insufficient to recommend routine testing at this time. As with all genetic testing, there are many factors to be considered. The tests themselves appear scientifically valid but more research is required to ascertain clinical effectiveness.