Warfarin (Coumadin) – CYP2C9 / VKORC1 / CYP4F2
Rationale
This drug gene interaction (DGI) pertains to the interaction between warfarin and three genes; vitamin K epoxide reductase complex subunit 1 (VKORC1) gene, the Cytochrome P450 2C9 (CYP2C9) gene, and the Cytochrome P450 4F2 (CYP4F2) gene. Warfarin (brand name Coumadin®) 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 requirements. Genetic results can assist in the selection of an optimal starting dose of warfarin. Providers can use a dosing algorithm to take patient’s genetic results and clinical factors into account when recommending a starting warfarin dose. The Gage dosing algorithm is widely used and recommended by CPIC. This algorithm combines the VKORC1, CYP2C9, and CYP2F2 genes mentioned above with non-genetic clinical datahttps://cpicpgx.org/guidelines/guideline-for-warfarin-and-cyp2c9-and-vkorc1/ (age, weight, sex, other medications) to provide a more accurate dose.1,2,3 Visit WarfarinDosing.org for more information about the Gage dosing algorithm.
Information presented on this page is based on evidence provided by the Clinical Pharmacogenomics Implementation Consortium (CPIC®). CPIC provides peer-reviewed, updated, evidence-based, and freely accessible guidelines for implementing pharmacogenomic results into actionable prescribing decisions for providers. CPIC guidelines include standardized terminology and a systematic grading of evidence and clinical recommendations published in a leading journal (Clinical Pharmacology and Therapeutics).
Genetic Variant Information
The CYP2C9 (sounds like “sip-2-see-9”) gene encodes the CYP2C9 enzyme, which is a member of the cytochrome P450 enzyme family. There are different forms of the CYP2C9 gene, or variants, that affect how well warfarin is metabolized. Some genetic variants result in a non-functioning or decreased functioning CYP2C9 enzyme, while other variants result in a normal functioning CYP2C9 enzyme. To see a list of variants and proposed functional status, visit CPIC and click on CYP2C9 under Allele Definition Table.
The VKORC1 (sounds like “vee-cor-see-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 forms of the VKORC1 gene, or variants, that affect how well warfarin is metabolized. 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 click on VKORC1 under Allele Definition Table.
The CYP4F2 (sounds like “sip-4-ehf-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 forms of the CYP4F2 gene, or variants, that affect how well warfarin is metabolized. Some genetic variants result in a non-functioning or decreased functioning CYP4F2 enzyme, while other variants result in a normal functioning CYP4F2 enzyme. To see a list of variants and proposed functional status, visit CPIC and click on CYP4F2 under Allele Definition Table.
Results Interpretation
Warfarin is a medicine used to manage your risk of blood clots and your genes can affect how well the drug works. CPIC updates guidelines on how to best use these genetic results to support patient care. To view dosing recommendations for warfarin based on CYP2C9, VKORC1, and CYP4F2 genotypes, click on the most recent guideline publication on CPIC’s website and scroll down to Figure 2.
Please review the FDA packet insert for additional clinical considerations such as contradictions as well as dose adjustments based on genetics, age, organ function, and drug-drug interactions.
The FDA strongly recommends regular monitoring of the patient’s International Normalcy Ratio (INR) throughout treatment.
Quality of Results
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%.
Supporting Evidence
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.
Please use the following links for more information on the Gage calculator.
- Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin
- Effect of Genotype-Guided Warfarin Dosing on Clinical Events and Anticoagulation Control Among Patients Undergoing Hip or Knee Arthroplasty
- Warfarin Dosing in Patients With CYP2C9*5 Variant Alleles
For more information on drug-gene interactions, please use the search feature on the CPIC website.