Whole Blood

3ml

lavender top (EDTA), pink (K2EDTA), blue (Na Citrate) or yellow (Acid Citrate Dextrose) collection tube

1ml

Ambient

30 days

Incorrect tube, Inadequate volume

Negative

1-7 days, please contact Molecular Diagnostics (409-772-4197) for quicker result.

Genmark eSensor

Molecular Diagnostics Laboratory

Warfarin, Coumadin, Warfarin Sensitivity, CYP2C9, 2C9, Cytochrome P450 2C9, P450 2C9 Genotyping, Vitamin K Epoxide Reductase Complex, VKORC1

81227, 81355

• Patient Consent Form

Characteristics: Warfarin (Coumadin) is metabolized primarily in the liver by cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and exerts its anticoagulant effect by inhibiting vitamin K epoxide reductase complex, subunit 1 (VKORC1). Three single nucleotide polymorphisms, two in the CYP2C9 and one in the VKORC1 genes, have been found to play key roles in determining the effect of warfarin therapy on coagulation. This test may predict individual warfarin sensitivity and non-standard dose requirements.

Inheritance: Autosomal co-dominant.
 

Variants Tested:

CYP2C9 (variants are numbered according to NM_000771): *2 (rs1799853, c.430C>T) and *3 (rs1057910, c.1075A>C). CYP2C9 *2 and *3 variants result in decreased enzyme activity that will reduce metabolism and prolong the half-life of warfarin. Negative, *1 (reference allele at all positions).

VKORC1 (variant is numbered according to NM_024006): VKORC1-1639 G>A polymorphism (rs9923231, c.-1639G>A). The VKORC1-1639A allele is associated with reduced expression of VKORC1 and a reduced dose requirement. Negative, the common VKORC1-1639G allele.

 Allele Frequencies:

CYP2C9: 11% and 7% of Caucasians carry the *2 and *3 variants, respectively. Both variants are rare (< 2%) in African Americans or Asians.

VKORC1-1639A: Caucasians 37 percent, Asians 91 percent, African Americans 14 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: Multiplex polymerase chain reaction and eSensor XT-8 System (GenMark Diagnostics). The U.S. Food and Drug Administration (FDA) has approved or cleared this test.

 Analytical Sensitivity and Specificity: 99 percent.
 

Limitations: Only the targeted CYP2C9 and VKORC1 variants 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.
 

Table 1. Expected maintenance warfarin daily doses (mg/day) based on CYP2C9 and VKORC1 genotypes (reproduced from updated warfarin FDA product label)

References:

OMIM: http://omim.org/entry/601130, and http://omim.org/entry/608547    

PharmGKB: https://www.pharmgkb.org/, updated Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines.

Warfarin and CYP2C9/VKORC1: https://www.pharmgkb.org/molecule/PA451906

CYP2C9: https://www.pharmgkb.org/gene/PA126

VKORC1: https://www.pharmgkb.org/gene/PA133787052

WarfarinDosing.org: http://www.warfarindosing.org/Source/Home.aspx

Counseling and informed consent are recommended for genetic testing.