VKORC1

Warfarin acts by inhibiting vitamin K epoxide reductase (VKOR) which limits the availability of reduced vitamin K, and therefore prevents the formation of functionally mature vitamin K-dependent clotting factors. VKOR is encoded by the VKORC1 gene. VKORC1 gene variants have been associated with both reduced and increased warfarin requirements.

Currently, the -1639G>A VKORC1 variant is the most useful predictor for identifying individuals who have an increased sensitivity to warfarin and may require a lower warfarin maintenance dose. This VKORC1 variant appears to cause reduced transcription of the VKOR gene product¹. Therefore, individuals with the -1639G>A variant (G/A or A/A) have naturally reduced levels of the VKOR enzyme and will be more sensitive to further inhibition of VKOR by warfarin.

CYP2C9

Warfarin is a racemic mixture of R- and S-enantiomers. S-warfarin accounts for most of the anticoagulant response. CYP2C9 is the major enzyme involved in S-warfarin metabolism. The CYP2C9 gene is highly polymorphic, with at least 50 different polymorphisms having been identified².

Two well-defined variants in the CYP2C9 gene significantly impact warfarin metabolism and are are denoted *2 and *3. The “normal” form of the gene is denoted *1. The CYP2C9*2 variant reduces the metabolism of warfarin by 30% to 50% while the CYP2C9*3 variant reduces metabolism by 90%^3,4.

Other Variants

At least 30 different genes are postulated to play a role in warfarin response⁵. However, variants of these genes appear to have a relatively small effect on how individuals respond to warfarin, and do not currently warrant clinical testing. This certainly may change in the future. Much of the current research has been performed in Caucasian populations. Additional variants in VKORC1, CYP2C9, or other genes may be found to be useful -- particularly in non-Caucasian ethnic groups.

DNA Direct is committed to providing the most comprehensive panel of variants shown to have clinical utility for predicting warfarin response. The warfarin response panel will be expanded as needed if additional variants are found to warrant testing.