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Test ID WARFB Warfarin Sensitivity Genotype by Sequence Analysis, Blood

Useful For

Identifying patients who may require warfarin dosing adjustments(2,3) including:

-Patients who have previously been prescribed warfarin and have required multiple dosing adjustments to maintain the international normalized ratio in the target range

-Patients with a history of thrombosis or bleeding when taking warfarin

-Patients being started on a first prescription for warfarin

Method Name

Polymerase Chain Reaction (PCR) Followed by DNA Sequence Analysis

Reporting Name

Warfarin Sensitivity Genotype, B

Specimen Type

Whole Blood EDTA

Multiple whole blood EDTA genotype tests can be performed on a single specimen after a single extraction. See Multiple Whole Blood EDTA Genotype Tests in Special Instructions for a list of tests that can be ordered together.

 

Container/Tube: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions: Send specimen in original tube.

Additional Information: If using drugs other than warfarin, order 2C9B / Cytochrome P450 2C9 Genotype by Sequence Analysis, Blood which only includes testing for the CYP2C9 gene.

Forms:

1. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

2. If not ordering electronically, complete, print, and send 1 of the following forms with the specimen:

Neurology Test Request Form-General (T732) (http://www.mayomedicallaboratories.com/it-mmfiles/neurology-request-form.pdf)

Cardiovascular Test Request Form (T724) (http://www.mayomedicallaboratories.com/it-mmfiles/cardiovascular-request-form.pdf)

Specimen Minimum Volume

0.45 mL

Specimen Stability Information

Specimen Type Temperature Time
Whole Blood EDTA Ambient (preferred)
  Refrigerated 

Clinical Information

Warfarin is a Coumarin-based drug commonly utilized in anticoagulation therapy to prevent thrombosis due to inherited and acquired hemostatic disorders. The drug is also used in a number of other medical conditions and treatments including atrial fibrillation and hip replacement surgery. Warfarin acts by interfering with the metabolism of vitamin K, which is necessary for production of key coagulation factors. Warfarin inhibits vitamin K recycling by blocking its metabolism at the vitamin K-epoxide intermediate, thereby decreasing the amount of available vitamin K. Warfarin has a narrow therapeutic window; under medicating increases the risk for thrombosis and overmedicating increases the risk for cerebrovascular accidents. Warfarin therapy has one of the highest rates of severe adverse drug reactions.

 

Warfarin is dosed using nongenetic factors including gender, weight, and age, and is monitored by coagulation testing in order to maintain the international normalized ratio (INR) within specific limits. However, warfarin metabolism is highly variable and dependent upon genetic factors. Variants within 2 genes are known to affect the metabolism of warfarin and the dose needed to maintain the correct serum drug level and degree of anticoagulation.

 

The CYP2C9 gene encodes the cytochrome P450 2C9 (CYP2C9) enzyme that primarily metabolizes the more active isomer of warfarin (S-warfarin) to inactive products. Some CYP2C9 variants result in decreased enzymatic activity and may lead to increases in serum warfarin and overmedicating, driving the INR above the therapeutic target.

 

The second gene (VKORC1) encodes vitamin K epoxide reductase complex subunit-1 (VKORC1), a small transmembrane protein of the endoplasmic reticulum that is part of the vitamin K cycle and the target of warfarin therapy.(1) Vitamin K epoxide, a by-product of the carboxylation of blood coagulation factors, is reduced to vitamin K by VKORC1. A VKORC1 promoter variant leads to decreased expression of the gene, resulting in reduced availability of vitamin K. This may cause increases in serum warfarin and overmedicating, driving the INR above the therapeutic target.  

 

Thus, the presence of CYP2C9 and/or VKORC1 variants may result in the need for a reduced warfarin dose and more careful monitoring in order to maintain the target INR.

 

CYP2C9:

CYP2C9 metabolizes a wide variety of drugs including warfarin and phenytoin.

 

A number of specific CYP2C9 variants result in enzymatic deficiencies. The following information outlines the relationship between the variants detected in this assay and their effect on the activity of the enzyme:

 

CYP2C9 Allele

cDNA Nucleotide Change

Effect on Enzyme Metabolism

*1

None (wild type)

Extensive metabolizer (normal)

*2

430C->T

Reduced activity

*3

1075A->C

Minimal activity

*4

1076T->C

Reduced activity

*5

1080C->G

Reduced activity

*6

818delA

No activity

*8

449G->A

Substrate specific

*9

752A->G

Reduced activity

*11

1003C->T

Reduced activity

 

 

VKORC1:

The c.-1639 promoter variant is located in the second nucleotide of an E-Box (CANNTG) and its presence disrupts the consensus sequence, reducing promoter activity. In vitro experiments show a 44% higher transcription level of the G versus the A allele.(1) The c.-1639 G>A nucleotide change results in decreased gene expression and reduced enzyme activity.

 

Warfarin dosing may require adjustment dependent on CYP2C9 and VKORC1 genotype and predicted phenotype. Patients who are CYP2C9 poor metabolizers (reduced activity) may benefit from warfarin dose reductions or by being switched to other comparable drugs that are not metabolized primarily by CYP2C9. Refer to the drug label for additional information, available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=558b7a0d-5490-4c1b-802e-3ab3f1efe760

Reference Values

An interpretive report will be provided.

Cautions

Rare variants may be present and could lead to false-negative or false-positive results. If results obtained do not match the clinical findings (phenotype), additional testing should be considered.

 

Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA. 

                               

CYP2C9 or VKORC1 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient's CYP2C9 or VKORC1 status.

 

This assay should be ordered on patients who require decreased warfarin dosing to maintain the international normalized ratio in the therapeutic range.

 

This method may not detect all variants that result in altered activity. Therefore, absence of a detectable gene variant does not rule out the possibility that a patient has an altered CYP2C9 and/or VKORC1 metabolism due to other variants that cannot be detected with this method. Furthermore, when 2 or more gene variants are identified, the cis-/trans- status (whether the variants are on the same or opposite chromosomes) is not always known.  

 

Warfarin metabolism may be inhibited through drug-drug interactions, including amiodarone and some statins.

Day(s) Performed

Monday, Thursday; 8 a.m.

Report Available

5 days (Not reported Saturday or Sunday)

Performing Laboratory

Mayo Medical Laboratories in Rochester

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

81227-CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6)
81355-VKORC1 (vitamin K epoxide reductase complex, subunit 1) (eg, warfarin metabolism), gene analysis, common variants (eg, -1639/3673)

NY State Approved

Conditional