Warfarin - CYP2C9 and VKORC1

The drug warfarin (Coumadin® and others and generic products) is prescribed for patients with a history of heart attack, heart valve replacement, or irregular heartbeat. The drug is taken to decrease the body’s ability to form clots (clumps of hardened blood). Clots are dangerous because they can block the flow of blood to various parts of the body and starve cells of nutrients and oxygen. This may potentially cause a heart attack or stroke.

Vitamin K is a vital nutrient found in many foods. It primarily located in green leafy vegetables such as kale, spinach, squash, and broccoli. It is taken up into the body by diet, where it is activated and used for the formation of clots. Warfarin decreases the body’s ability to activate and use vitamin K in the formation of clots. Although clots are dangerous, a minimum level of clotting is needed to accomplish the body’s normal function. At appropriate doses, warfarin can help prevent heart attack or stroke by decreasing clot formation. However, high doses increase the risk of uncontrolled bleeding which can become life threatening. This is why maintaining an appropriate dose of warfarin is incredibly important.

There are two genes that are important for warfarin’s effect in the body. The first gene provides instructions for making what is known as a cytochrome (CYP) enzyme, specifically subtype 2C9 (CYP2C9, pronounced “sip two see nine”). This enzyme is responsible for the breakdown of warfarin into its inactive form. The second gene provides instructions for making an enzyme that is responsible for activating vitamin K. This enzyme is called vitamin K epoxide reductase complex subtype 1 (VKORC1, pronounced “vee cor see one”).

Genetic variability in the genes encoding CYP2C9 and VKORC1 between patients lead to differences in the individual patient’s response to warfarin treatment. This may make dose adjustment necessary. Variation in the CYP2C9 gene may result in patients with decreased ability to break down warfarin, and this will leave more active drug in the body. Therefore, patients with this variation require lower doses of warfarin to avoid having an increased risk of uncontrolled bleeding. This CYP2C9 gene difference is more commonly found in Caucasians than African-Americans and Asians.

Variation in the VKORC1 gene results in decreased ability to activate and use vitamin K in forming clots. Therefore, patients with this variation require lower doses of warfarin to avoid increased risk of uncontrolled bleeding. This genetic variant of the VKORC1 gene is most commonly found in Asians and least commonly in African Americans.

In general, the effect of VKORC1 gene variation is more often responsible for warfarin dose differences between individuals than is CYP2C9, but both variants should be considered for optimal dose selection. A genetic test is available to tell if CYP2C9 or VKORC1 variation is present.

A Caucasian male, William, is prescribed warfarin following a heart attack. His doctor tells him about the necessary international normalized ratio (INR) monitoring, with his goal level being between 2 and 3. This helps the doctor know how fast William’s blood is clotting, and therefore how appropriate his warfarin dose is. Although his doctor explained the genetics of CYP2C9 and VKORC1, William decides not to undergo genetic testing and assures his doctor he will follow up for monitoring. Even after adjusting the dose multiple times, it is difficult to keep William within normal INR limits. One day, William experiences persistent bleeding from the gums and is admitted to the emergency room for vitamin K rescue therapy. Genetic testing reveals that William has the CYP2C9 variant that decreases the breakdown of warfarin into its inactive form. After his recovery, the doctor further reduces the dose of Warfarin and continues to monitor William’s INR frequently.

An Asian female, Crystal, is on warfarin for an irregular heartbeat. She has heard that there can be risks of bleeding while on this therapy and that these risks have an association with genetics. Crystal also has a cousin that is on a lower dose because of a genetic variation. After talking with her doctor, Crystal decides to undergo genetic testing and it is revealed that she has the VKORC1 genotype that could increase her chances of bleeding. With this information, her doctor is able to select an appropriate lower warfarin dose for Crystal to maximize the medication’s benefit while decreasing its bleeding risks.

CYP2C9 and VKORC1 genetic testing does not completely rule out the risks of taking warfarin, nor does it guarantee the medication will work for you. Genetic testing is a guide to personalize the treatment of patients, maximizing benefit and minimizing harm.

The links below provide access to important articles and information relative to warfarin. The links are to external websites and will be checked regularly for consistency.

• Warfarin Prescribing Information
• Warfarin Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: Warfarin

DailyMed [Internet]. Bethesda (MD): U.S. National Library of Medicine; c1993-2015. Warfarin Sodium; [cited 2012 Oct 23]; [about 4 screens]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=558b7a0d-5490-4c1b-802e-3ab3f1efe760/.

Gage BF and Lesko LJ. Pharmacogenetics of Warfarin: Regulatory, Scientific, and Clinical Issues. J Thromb Thrombolysis. 2008 Feb;25(1):45-51.

Hirsh J, Dalen J, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001 Jan;119(1 Suppl):8S-21S.

Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther. 2011 Oct;90(4):625-9.

Peristein TS, Goldhaber SZ, Nelson K, et al. The Creating an Optimal Warfarin Nomogram (CROWN) Study. Thromb Haemost. 2012 Jan; 107(1): 59-68.

PharmGKB [Internet]. Stanford (CA): U.S. Department of Health and Human Services; c2001-2015. Warfarin; [cited 2012 Oct 19]; [about 4 screens]. Available from: https://www.pharmgkb.org/chemical/PA451906/.

Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. 2005 Jun 2;352(22):2285-93.

Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: A HuGEnet systematic review and meta-analysis. Genet Med. 2005 Feb;7(2):97-104.

Stehle S, Kirchheiner J, Lazar A, Fuhr U. Pharmacogenetics of Oral Anticoagulants. Clin Pharmacokinet. 2008;47(9):565-94.