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Warfarin Sensitivity, CYP2C9 and VKORC1, 3 Variants
2012772
Ordering Recommendation

Identify individuals with inherited variants that affect metabolism and/or sensitivity to warfarin.

Mnemonic
WARFGENO
Methodology
Polymerase Chain Reaction/Fluorescence Monitoring
Performed
Mon, Thu
Reported
5-10 days
New York DOH Approval Status
This test is New York DOH approved.
Submit With Order
Specimen Required
Patient Preparation
 
Collect
Lavender (EDTA), pink (K2EDTA), or yellow (ACD Solution A or B). 
Specimen Preparation
Transport 3 mL whole blood. (Min: 1 mL) 
Storage/Transport Temperature
Refrigerated. 
Unacceptable Conditions
Plasma or serum. Heparinized specimens. 
Remarks
 
Stability
Ambient: 72 hours; Refrigerated: 2 weeks; Frozen: 1 month 
Reference Interval
By report
Interpretive Data
Background Information for Cytochrome P450 2C9, CYP2C9, 2 Variants:
Characteristics:
The cytochrome P450 (CYP) isozyme 2C9 is involved in the metabolism of many drugs such as warfarin, phenytoin, tolbutamide, glipizide, ibuprofen, and phenobarbital. Variants of CYP2C9 will influence pharmacokinetics of CYP2C9 substrates, and may predict non-standard dose requirements.
Inheritance: Autosomal co-dominant.
Cause:CYP2C9 gene variants result in decreased or complete deficiency in enzyme activity.
Variants Tested:
(
Variants are numbered according to NM_000771 transcript)
Decreased function: *2 (rs1799853, c.430C>T).
Non-functional: *3 (rs1057910, c.1075A>C).
Negative: No variants detected is predictive of *1 functional alleles and normal enzymatic activity.
Allele Frequencies:
CYP2C9 *2: Caucasians 13 percent, Asians<1 percent, African Americans 3 percent.
CYP2C9 *3: Caucasians 7 percent, Asians 4 percent, African Americans 2 percent.
Clinical Sensitivity: Drug-dependent.
Methodology: Polymerase chain reaction (PCR) and fluorescence monitoring.
Analytical Sensitivity and Specificity: Greater than 99 percent.
Limitations: Only the targeted CYP2C9 variants will be detected by this panel. Diagnostic errors can occur due to rare sequence variations. Risk of therapeutic failure or adverse reactions with CYP2C9 substrates may be affected by genetic and non-genetic factors that are not detected by this test. This result does not replace the need for therapeutic drug or clinical monitoring.

Background Information for Warfarin Sensitivity by VKORC1, 1 Variant:
Characteristics:
Warfarin sensitivity can lead to a life-threatening overdose event such as excessive bleeding. Genetic variation is recognized to explain a large proportion of variability in warfarin dose requirements. This test may predict individual warfarin sensitivity and non-standard dose requirements. The VKORC1 test should be performed in combination with the CYP2C9 test for application to warfarin dose estimates, such as through www.WarfarinDosing.org .
Inheritance: Autosomal co-dominant.
Cause: The VKORC1*2 allele is associated with reduced expression of the warfarin target, vitamin K epoxide reductase (VKOR), and a reduced dose requirement. CYP2C9 gene variants result in decreased or complete deficiency in enzyme activity that will reduce metabolism and prolong the half-life of warfarin.
Variants Tested:VKORC1*2 (rs9923231, c.-1639G>A).
(Note: Variant is numbered according to VKORC1transcript NM_024006.)
Negative: No variant detected is predictive of *1 functional allele and normal VKOR expression.
Allele Frequencies:
VKORC1*2: Caucasians 39 percent, Asians 91 percent, African Americans 11 percent.
Clinical Sensitivity: Approximately 90 percent of CYP2C9 and VKORC1 variants causing warfarin sensitivity in Caucasians are detected when both tests are performed. Less characterized in other populations.
Methodology: Polymerase chain reaction(PCR) and fluorescence monitoring.
Analytical Sensitivity and Specificity: Greater than 99 percent.
Limitations: Only the targeted VKORC1 variant will be detected by this test. Diagnostic errors can occur due to rare sequence variations. Risk of therapeutic failure or adverse reactions with warfarin may be affected by genetic and non-genetic factors that are not detected by this test. This result does not replace the need for therapeutic drug or clinical monitoring. This test does not identify patients at risk for warfarin resistance.

Compliance Statement C: The performance characteristics of this test were validated by ARUP Laboratories. The U.S. Food and Drug Administration (FDA) has not approved or cleared this test. However, FDA approval or clearance is currently not required for clinical use of this test. The results are not intended to be used as the sole means for clinical diagnosis or patient management decisions. ARUP is authorized under Clinical Laboratory Improvement Amendments (CLIA) and by all states to perform high-complexity testing. Counseling and informed consent are recommended for genetic testing. Consent forms are available online.

Components
Component Test Code*Component Chart NameLOINC
2008930CYP2C9 Genotype
2008931CYP2C9 Phenotype
2012773WARF GENO Specimen
2012775VKORC1 Genotype
2012776Warfarin Predicted Sensitivity
* Component test codes cannot be used to order tests. The information provided here is not sufficient for interface builds; for a complete test mix, please click the sidebar link to access the Interface Map.
Aliases