How does warfarin work?
Warfarin decreases blood coagulation by inhibiting the vitamin K epoxide reductase, encoded by the VKORC1 gene. Vitamin K1 plays a major role in blood clotting and is often used to prevent “blood thinning”. The VKORC1 enzyme recycles inactive vitamin K1 after it has helped to activate several proteins involved in clotting. Warfarin prevents this vitamin K1 recycling, thereby depleting active vitamin K1.

Warfarin activity must be monitored carefully to ensure that an adequate and safe dose is taken each day. It is monitored by blood testing to determine the international normalized ratio (INR). If the INR is too high, there is an increased risk of abnormal bleeding (haemorrhage). If the INR is too low, it indicates that the dose is insufficient to protect against blood clots.

What genetic variants affect warfarin dose?
Multiple genetic differences across four genes affect the dose required to achieve a stable INR:

• VKORC1 – encodes a blood clotting enzyme (the target of warfarin)
• CYP2C9 – encodes the primary metabolizer of warfarin
• GGCX – encodes a blood clotting enzyme
• CYP4F2 – encodes an enzyme that breaks down active vitamin K1

How are the genetic variants inherited?
The VKORC1, CYP2C9, GGCX and CYP4F2 genes are all located on autosomal chromosomes and we each inherit two copies of all the genes on the autosomal chromosomes. Therefore we can inherit two normal copies of a gene (homozygous normal), or two copies that carry the same genetic variation (homozygous variant), or one normal copy and one variant copy (heterozygous). This means that we can inherit several different combinations of the VKORC1, CYP2C9, GGCX and CYP4F2 genes and each combination affects the required warfarin dosage.

DNA testing for warfarin dosing
A simple DNA test can be completed to find out which versions of VKORC1, CYP2C9, GGCX and CYP4F2 genes were inherited. The warfarin dosing DNA test examines eleven markers across the four genes. The results of this analysis significantly reduce the time taken to achieve a safe and stable level of blood anticoagulation, and reduce the risks of potentially life-threatening problems.

The genetic information obtained from the DNA test for warfarin dosing, along with patient information (including age, gender, height, weight, race, and current medications), is entered into an online table provided by WarfarinDosing.org. WarfarinDosing.org uses this data in an algorithm to determine the initial Warfarin dose and subsequent daily doses required to achieve the target international normalized ratio (INR).