Warfarin (P450 2C9 and VKORC1)

CPT: 81227; 81355
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Test Details

Synonyms

  • DME Genotyping

Use

Warfarin, the coumadin derivative, is the most widely prescribed anticoagulant for thromboembolic disorders.

Limitations

The metabolism of drugs is also influenced by ethnicity, diet, and other medications. All factors should be considered prior to initiating new therapy.

Methodology

Real-time polymerase chain reaction (PCR)

Additional Information

VKORC1 (vitamin K epoxide reductase complex subunit 1) and cytochrome P450 CYP2C9 account for as much as 50% of the interindividual variability of the warfarin response. These genetic markers may serve as clinically relevant predictors of warfarin dosing.

The presence of the promoter mutation -1639G>A in the VKORC1 gene reduces the gene's expression and leads to combined deficiency of vitamin K-dependent coagulation factors type 2 (VKCFD2). The risk of bleeding complication during oral anticoagulation is high. Low-dosage warfarin treatment should be considered. Analysis of the VKORC1 gene targets the 1173C>T mutation, which is in linkage disequilibrium with -1639G>A and thus carries identical diagnostic utility.

The presence of the *2 and/or *3 alleles in the CYP2C9 gene can result in poor metabolizer (PM) phenotypes. The PM phenotype is associated with lack of enzyme activity, and the drug may be metabolized slowly or not at all. This results in increased concentrations of the drug with a reduced or absent therapeutic response and the potential for serious side effects. Warfarin metabolism is reduced by 30% to 50% by the *2 allele and 90% by the *3 allele. This affect may be more pronounced in Asians as compared to Caucasians. Individuals with at least one copy of *2 or *3 have an increased risk of bleeding compared to individuals without *2 or *3. A lower maintenance dose may be required. Coadministration of inhibitors of CYP2C9, such as phenylbutazone, sulfinpyrazone, amiodarone, miconazole, isoniazid, ticlopidine, tamoxifen, or fluconazole, will increase the anticoagulation effect. The azole antifungal agent fluconazole (Diflucan) is a potent inhibitor of CYP2C9. Fluconazole, at conventional doses, abolishes CYP2C9 activity. Rifampin, barbiturates, carbamazepine, and St John's Wort will increase warfarin metabolism and increase the chance of reduced efficacy, and the warfarin dose may need to be increased.

Specimen Requirements

Specimen

Whole blood or LabCorp buccal swab kit (buccal swab collection kit contains instructions for use of a buccal swab)

Volume

7 mL whole blood or LabCorp buccal swab kit

Minimum Volume

3 mL whole blood or two buccal swabs

Container

Lavender-top (EDTA) tube, yellow-top (ACD) tube, or LabCorp buccal swab kit

Storage Instructions

Maintain specimen at room temperature or refrigerate at 4°C.

Causes for Rejection

Frozen specimen; hemolysis; quantity not sufficient for analysis; improper container; one buccal swab; wet buccal swab

Clinical Information

References

Adcock DM, Koftan C, Crisan D, Kiechle FL. Effect of polymorphisms in the cytochrome P450 CYP2C9 gene on warfarin anticoagulation. Arch Pathol Lab Med. 2004 Dec; 128(12):1360-1363.15578879
Blue Cross Blue Shield Association Technology Evaluation Center Assessment Program. Special Report: Genotyping for Cytochrome P450 Polymorphisms to Determine Drug-Metabolizer Status. Vol 19, N° 9, December 2004.15578879
Gage BF, Eby C, Milligan PE, Banet GA, Duncan JR, McLeod HL. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost. 2004 Jan; 91(1):87-94.14691573
Kirchheiner J, Brockmöller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther. 2005 Jan; 77(1):1-16.15637526
Rost S, Fregin A, Ivaskevicius V, et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature. 2004 Feb 5; 427(6974):537-541.14765194
Voora D, Eby C, Linder MW, et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb Haemost. 2005 Apr; 93(4):700-705.15841315

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
511460 Warfarin (p450 2C9 and VKORC1) 511461 2C9 Genotype 46724-1
511460 Warfarin (p450 2C9 and VKORC1) 511462 VKORC1 Genotype 50722-8
511460 Warfarin (p450 2C9 and VKORC1) 511466 Interpretation: 62365-2
511460 Warfarin (p450 2C9 and VKORC1) 511467 Comment: N/A
511460 Warfarin (p450 2C9 and VKORC1) 511471 Methodology: 49549-9
511460 Warfarin (p450 2C9 and VKORC1) 511469 Director Review: 72486-4

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