This DGI pertains to the interaction between the vitamin K epoxide reductase complex subunit 1 (VKORC1) gene, the Cytochrome P450 Family 2 Subfamily C Member 9 (CYP2C9) gene, the Cytochrome P450 Family 4 Subfamily F Member 2 (CYP4F2) gene, and warfarin. Warfarin works by decreasing the body’s ability to form blood clots by blocking the formation of vitamin K-dependent clotting factors that are necessary to form clots.
Extensive literature and FDA warning labels indicate that specific variations in these genes affect warfarin dose variability. Genetic results can assist in the selection of a safe and effective starting dose of warfarin. This DGI provides a dosing algorithm that considers the VKORC1 and CYP2C9 genes mentioned above as well as clinical factors. The inclusion of CYP4F2 gene variations in dosing calculations are considered optional, but are also referenced below.
The CYP2C9 (sounds like “sip-2-C-9”) gene encodes the CYP2C9 enzyme, which is a member of the cytochrome P450 enzyme family. There are different CYP2C9 gene versions, or variants, and each has a different effect on how well warfarin is metabolized in the body. Some variants result in a non-functioning or low-functioning CYP2C9 protein while other variants result in a normal-functioning CYP2C19 protein. To see a list of variants and proposed functional status, visit CPIC and scroll down to click on “CYP2C9_allele_definition_table”.
The VKORC1 (sounds like “vee-cork-1) gene encodes the VKORC1 enzyme, which is a key enzyme in the vitamin K cycle. VKORC1 is responsible for creating clotting factors. There are different VKORC1 gene versions, or variants, and each has a different effect on how well warfarin is metabolized in the body. One specific VKORC1 variant (rs9923231) is associated with warfarin sensitivity and requires a lower warfarin dose. To see a list of variants and proposed functional status, visit CPIC and scroll down to click on “VKORC1_allele_definition_table”.
The CYP4F2 (sounds like “sip-4-F-2”) gene encodes the CYP4F2 enzyme, which is a member of the cytochrome P450 enzyme family and acts to remove vitamin K from the vitamin K cycle. CYP4F2 is an important counterpart to VKORC1 in limiting excessive accumulation of vitamin K. There are different CYP4F2 gene versions, or variants, and each has a different effect on how well warfarin is metabolized in the body. Some variants result in a low-functioning CYP4F2 protein while other variants result in a normal-functioning or increased function CYP4F2 protein. To see a list of variants and proposed functional status, visit CPIC and scroll down to click on “CYP4F2_allele_definition_table”.
Figure 2 in the CPIC Guideline Paper describes a dosing recommendation workflow based on genotype for adult patients. Figure 3 describes a dosing recommendation workflow based on genotype for pediatric patients.
Genotyping for VKORC1, CYP2C9 and CYP4F2 was performed within a certified DNA laboratory at Vanderbilt University Medical Center that is in full compliance with all guidelines established by the government as regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Act of 1988. This validated clinical laboratory developed test is carried out with strict adherence to protocols outlined by the College of American Pathology. The performance of the assay is closely monitored and the accuracy of the results is determined to be > 99%.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Pharmacogenetics-Guided Warfarin Dosing
This link will take you to the main page on the CPIC website relating to CYP2C9, VKORC1, CYP4F2 and warfarin. On the site, you will find links to the main guideline publication and all supplementary information including a table that reports variant frequencies across different races/ethnic groups, a table that defines genetic variants, and a table that provides functional statuses associated with alleles.
For more information on drug-gene interactions, please use the search feature on the CPIC website.