Sorted By Test Name - Mayo Medical Laboratories

WARFO
60341
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 polymorphism in order to maintain the target INR.
CYP2C9 CYP2C9 metabolizes a wide variety of drugs including warfarin and many nonsteroidal
anti-inflammatory drugs. It is also partially responsible for metabolizing other drugs such as fluoxetine,
fluvastatin, phenytoin, and oral hypoglycemic drugs. A number of specific polymorphisms have been
found in the CYP2C9 gene that result in enzymatic deficiencies. The following information outlines the
relationship between the polymorphisms detected in this assay and the effect on the activity of the enzyme
encoded by that allele: CYP2C9 Allele 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 Dosing of warfarin,
which is metabolized through CYP2C9, may require adjustment for the individual patient. Patients who
are poor metabolizers (reduced activity) may benefit by dose reductions or by being switched to other
comparable drugs that are not metabolized primarily by CYP2C9. The following is a partial listing of
drugs known to affect CYP2C9 activity as of the date of this report. A more complete listing is presented
in the drug label, available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/009218s108lbl.pdf Drugs that undergo
metabolism by CYP2C9: -Angiotensin II blockers: irbesartan, losartan -Anticoagulants: warfarin (more
active S-isomer) -Antidepressants: amitriptyline (minor), fluoxetine -Nonsteroidal anti-inflammatory
drugs (NSAIDS): celecoxib, diclofenac, ibuprofen, naproxen, piroxicam, suprofen -Oral hypoglycemic
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