WARFARIN SENSITIVITY GENOTYPING

DNA ANALYSIS

Coumadin (Warfarin) is a commonly prescribed anticoagulant used to prevent thrombosis and as prophylaxis in individuals who are susceptible to or have already formed thrombi or emboli. Common clinical indications for long-term treatment with Warfarin include atrial fibrillation and deep venous thrombosis. Warfarin acts on the vitamin K epoxide reductase complex subunit 1 to decrease the amount of available vitamin K for coagulation. Warfarin has a narrow therapeutic window which must be closely monitored in order to optimize efficacy and reduce the risk of adverse effects, such as bleeding. It is well known that certain medications and foods can alter the effect of Warfarin and patients are instructed to avoid these items. In addition, it is now known that genetic variations in two genes, cytochrome p450 2C9 (CYP2C9) and vitamin K epoxide reductase complex, subunit 1 (VKORC1) may also alter the metabolism of Warfarin. In August 2007, the FDA approved a change for the labeling of Warfarin to include information that certain variants in the CYP2C9 and VKORC1 genes may alter Warfarin metabolism.

Warfarin is metabolized by CYP2C9. Nucleotide variations occurring in the CYP2C9 gene affect enzyme activity. Decreased activity of CYP2C9 results in a higher active form of Warfarin in the body due to slow metabolism, therefore increasing the risk of bleeding. Genetic variations in the VKORC gene cause a reduced production of the enzyme and decreased amount of vitamin K for coagulation. Identification of variants in these genes may result in reduced enzymatic activity, thereby requiring lower doses for effective and safe anticoagulation.

This analysis tests for seven genetic variations in the CYP2C9 and VKORC1 genes.

Reasons For Referral:

Patients starting initial treatment with Warfarin
Patients already treated with Warfarin who are experiencing difficulty in achieving therapeutic INR
The results of this test can be used in available algorithms to determine appropriate Warfarin dosing (example)

Limitations:

Not all variants with known impact on enzyme expression and activity are tested in this assay. .
Non-genetic factors, variations in the other genes involving the drug metabolism or drug interactions are not measured by this assay.
Rare genetic alterations at primer binding sites may result in diagnostic errors.

Testing Methodology:

This analysis incorporates DNA amplification by multiplex PCR, allele specific primer extension, microarray hybridization and Fluorescence signal detection.

Variant alleles tested:

CYP2C9:

2 (c.430C>T, p.R144C)- Decreased activity
3 (c.1075A>C, p.I359L)- Decreased activity
4 (c.1076T>C)- Decreased activity
5 (c.1080C>G, p.D360E)- Decreased activity
6 (c.808delA)- No activity
11 (100C>T), decreased activity

VKORC1:

1639G>A- Decreased activity

Analytical Sensitivity and Specificity:

Greater than 99%

Specimen Requirements:

Blood: EDTA (purple-top) tubes: Adults: 3cc.
Requisition form must accompany specimen. Prior to any genetic testing, we recommend genetic counseling and request that the subject sign our consent form and submit it with the sample. To receive our forms, additional information, or kits, please contact to our laboratory.

Turnaround Time:

7 days

CPT Codes and Prices:

Index: 83891, 83900, 83901x5, 83914x14, 83912

Shipping Information

Forms:

>> DNA Requisition

References:

Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, Wood P, Kesteven P, Daly AK, Kamali F. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 2005 Oct 1; 106(7): 2329-33.
Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, Lu MJ, Hung CR, Wei CY, Chen CH, Wu JY, Chen YT. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet. 2005 Jul 1; 14(13): 1745-51.
International Warfarin Pharmacogenetics Consortium, Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009 Feb 19; 360(8): 753-64.

Test Codes:

Index: 6880