Mayo Test Catalog, (Sorted By Test Name) - Mayo Medical ...

WARFO
60341
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 previously taking warfarin -Patients being started on a first prescription for warfarin
Interpretation: An interpretive report will be provided. The normal genotype (wild-type) for
CYP2C9 is termed CYP2C9*1. Other genotypes that lead to inactive or reduced activity alleles include
CYP2C9*2, CYP2C9*3, CYP2C9*4, CYP2C9*5, and CYP2C9*6. An individual who has homozygous
wild-type, CYP2C9*1/CYP2C9*1, is considered an extensive metabolizer. The normal genotype for
VKORC1 is -1639G. A polymorphism at -1639A reduces VKORC1 expression. The VKORC1 GA or
AA genotype leads to a significant decrease in mRNA expression in the liver compared with individuals
with the GG genotype. Individuals who have polymorphisms in both the VKORC1 promoter (GA or
AA) and also in CYP2C9 should receive a reduced dose of warfarin to maintain the international
normalized ratio in the target range; dosing adjustments are required when polymorphisms in both genes
are present. Drug-drug interactions and drug-metabolite inhibition must be considered when dealing
with heterozygous individuals. Drug-metabolite inhibition can occur, resulting in inhibition of residual
functional CYP2C9 or VKORC1 catalytic activity. A clinical pharmacologist should be consulted for
assessing the potential for drug interactions. Patients may also develop toxicity problems if liver and
kidney function are impaired.
Reference Values:
An interpretive report will be provided.
Clinical References: 1. Oldenburg J, Bevens C, Muller C, Watzka M: Vitamin K epoxide
reductase complex subunit I (VKORC1): the key protein of the vitamin K cycle. Antioxid Redox Signal
2006;8(3-4):347-353 2. Yuan H, Chen J, Lee M, et al: A novel functional VKORC1 promoter
polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity.
Hum Mol Genet 2005;14:1745-1751 3. Sconce E, Khan T, Wynne H, et al: The impact of CYP2C9 and
VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements proposal
for a new dosing regimen. Blood 2005;106:2329-2333
Warfarin Sensitivity Genotype by Sequence Analysis, Saliva
Clinical Information: Warfarin is a Coumadin-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 interfacing 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; undermedicating 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. Polymorphisms 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, as
measured by the INR. The cytochrome P450 2C9 gene (CYP2C9) encodes an enzyme that metabolizes
the more active isomer of warfarin (S-warfarin) to inactive products. Polymorphisms in this gene
decrease the activity of the enzyme and may cause increases in serum warfarin and overmedicating,
driving INR above the therapeutic target level. 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) VKORC1 is primarily
transcribed in the liver, although it is present in smaller amounts in the heart and pancreas. Vitamin K
epoxide, a by-product of the carboxylation of blood coagulation factors, is reduced to vitamin K by
VKORC1. A polymorphism within the promoter of VKORC1 decreases expression of the gene,
decreasing the availability of vitamin K. This may cause increases in serum warfarin and
overmedicating, driving INR above the therapeutic target level. Thus, in both situations (polymorphisms
in either CYP2C9 or VKORC1), a reduced warfarin dose is needed to compensate for the effects of the
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