Warfarin resistance; Coumarin resistance - VKORC1, ABCB1, CALU, CYP2A6, CYP4F2, NQO1 and UGT1A1 genes

Warfarin resistance, also known as coumarin resistance, is an alteration in which affected individuals have a high tolerance to the warfarin drug. Warfarin is an anticoagulant, which is often prescribed to prevent the formation of blood clots in people with heart valve disease, people with atrial fibrillation, or those with a history of myocardial infarction, stroke, or deep vein thrombosis.

There are two types of resistance to warfarin related to how the body processes warfarin: incomplete and complete. In some people with resistance to warfarin, their blood coagulation process does not react effectively to the drug. Others metabolize warfarin quickly; these individuals are classified as "rapid metabolizers" of warfarin. The severity of these abnormal processes determines whether the resistance to warfarin is complete or incomplete. People with incomplete warfarin resistance may benefit from warfarin therapy with a high dose of warfarin. People with complete warfarin resistance do not respond to warfarin therapy, regardless of dose. If people with resistance to warfarin require treatment with warfarin and take the average dose, they will remain at risk of developing a potentially harmful blood clot.

Many genes are involved in the metabolism of warfarin and in determining the effects of the drug on the body. Certain polymorphisms in the VKORC1 gene (vitamin K epoxide reductase complex subunit 1) are responsible for 20% of the variation in the metabolism of warfarin due to genetic factors. Polymorphisms in other genes, some of which have not been identified, have a minor effect on the metabolism of warfarin. The known genes include the following genes: ABCB1 (ATP binding cassette subfamily B member 1), CALU (calumenin), CYP2A6 (cytochrome P450 family 2 subfamily A member 6), CYP4F2 (cytochrome P450 family 4 subfamily F member 2), NQO1 (NAD (P) H quinone dehydrogenase 1) and UGT1A1 (UDP glucuronosyltransferase family 1 member A1).

The VKORC1 gene, located on the short arm of chromosome 16 (16p11.2), encodes a vitamin K epoxide reductase. The VKORC1 enzyme helps activate coagulation proteins in the process that forms blood clots. Specifically, the enzyme VKORC1 converts a form of vitamin K into a different form of vitamin K that aids in the activation of the coagulation proteins. Certain polymorphisms of the VKORC1 gene result in the formation of a VKORC1 enzyme with a decreased ability to bind to warfarin. This reduction in warfarin binding causes incomplete resistance to warfarin and results in a greater need for warfarin to inhibit the VKORC1 enzyme and stop the clotting process. If warfarin cannot bind to the enzyme VKORC1, complete resistance to warfarin occurs. Thirty-two variations in the VKORC1 gene have been identified. The polymorphism of the most common VKORC1 gene in people with resistance to warfarin replaces the amino acid aspartic acid with the amino acid tyrosine at position 36 of the enzyme VKORC1 (Asp36Tyr or D36Y). While changes in specific genes affect how the body reacts to warfarin, many other factors, such as gender, age, weight, diet and other medications, also play a role in the body's interaction with this drug.


The polymorphisms associated with resistance to warfarin are inherited in an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to cause resistance to warfarin. However, different polymorphisms affect the activity of warfarin to varying degrees. Additionally, people who have more than one polymorphism in a gene or polymorphisms in multiple genes associated with resistance to warfarin have a greater tolerance for the effect of the drug or are able to process the drug more quickly.


Tests performed in IVAMI: in IVAMI perform the detection of mutations associated with resistance to warfarin, by complete PCR amplification of the exons of the VKORC1, ABCB1, CALU, CYP2A6, CYP4F2, NQO1 and UGT1A1 genes, and their subsequent sequencing.


Recommended samples: blood drawn with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).