Warfarin Sensitivity (CYP2C9, CYP2C cluster, CYP4F2, VKORC1) Genotyping

Last Literature Review: July 2019 Last Update:

Use to identify individuals with inherited variants that affect metabolism of (CYP2C9 and CYP2C cluster) and/or sensitivity to (CYP4F2, VKORC1) warfarin.

Refer to the Variants Tested table for more information.

Warfarin (Coumadin) is an anticoagulant widely used throughout the world.  Testing may be indicated for warfarin-naïve individuals prior to starting warfarin therapy, individuals with a personal or family history of difficulty with warfarin, and adherent patients taking warfarin but who are difficult to treat. Testing is also indicated for individuals currently on warfarin and required to discontinue therapy, such as prior to an invasive procedure or surgery, to estimate the time required to eliminate the drug. This test does not target variants associated with warfarin resistance.

Disease Overview

Pathophysiology

  • Warfarin's primary mechanism of action is to inhibit vitamin K epoxide reductase (VKOR).
    • VKOR recycles vitamin K and activates clotting factors II, VII, IX, and X.
  • Warfarin exerts anticoagulant effects by reducing the concentration of these activated clotting factors.

Diagnostic Issues

  • Individual response to warfarin varies:
    • Factors affecting response include age, gender, body mass, diet, concomitant medications, and genetic variants.
    • An estimated 40-63% of the variability in therapeutic warfarin dose is accounted for by the CYP2C9*2 and *3 and the VKORC1*2 variant alleles.
    • The CYP2C cluster variant, rs12777823, common in people of African descent, with a minor allele frequency of approximately 25%, is found to be associated with a decreased warfarin dose requirement in this population.
  • Overdosing and underdosing can result in life-threatening events (eg, bleeding or thrombosis).
    • Approximately 1% of individuals die due to bleeding complications associated with warfarin.
    • Approximately 15% of individuals experience minor bleeding complications.
  • Dose adjustments are often necessary.
    • Usually based on international normalized ratio (INR)
    • May be difficult to achieve therapeutic INR in some individuals (eg, those requiring <21 mg per week or >49 mg per week to maintain INR).

Genetics

Genes Tested

CYP2C9, CYP2C rs12777823, CYP4F2, VKORC1

Inheritance

Autosomal codominant

Variants Tested

Variants or groups of variants are classified as “star” (*) alleles for some genes such as CYP2C9, and functional phenotype is predicted based on international consensus nomenclature. However, not all variants on a chromosome/allele are interrogated and assumptions about phase are made, as shown below. More details about nomenclature, allele frequencies, and phenotype predictions are available at PharmVar  or PharmGKB .

Gene (Transcript)AllelesPredicted Allele Function
CYP2C cluster (NC_000010)CYP2C: rs12777823, g.96405502 G>AUnclassifieda
CYP2C9 (NM_000771)CYP2C9*2: rs1799853, c.430C>TDecreased function
CYP2C9*3: rs1057910, c.1075A>CNo function
CYP2C9*4: rs56165452, c.1076T>CDecreased function
CYP2C9*5: rs28371686, c.1080C>GDecreased function
CYP2C9*6: rs9332131, c.818delNo function
CYP2C9*8: rs7900194, c.449G>ADecreased function
CYP2C9*11: rs28371685, c.1003C>TDecreased function
CYP2C9*12: rs9332239, c.1465C>TDecreased function
CYP4F2 (NM_001082)CYP4F2*3: rs2108622, c.1297G>A (c.1275G>A b)Unclassifiedc
VKORC1 (NM_024006)VKORC1*2: rs9923231, c.-1639G>AWarfarin sensitivity

aThe CYP2C cluster variant is associated with a decreased warfarin dose requirement in some people of African descent.

bPharmVar annotation.

cThe CYP4F2 variant is associated with increased warfarin dose requirements, particularly during initiation.

Sources: PharmVar,  PharmGKB 

Test Interpretation

Sensitivity/Specificity

  • Clinical sensitivity: genetic factors and known non-genetic factors account for approximately 50% of the variability in warfarin dose 
  • Analytic sensitivity and specificity: >99%

Results

  • Variant(s) detected:
    • VKORC1*2 allele is associated with reduced expression of the warfarin target, vitamin K epoxide reductase (VKOR), and a reduced dose requirement.
    • The CYP4F2*3 allele is associated with an increased dose requirement.
    • CYP2C9 variants are associated with a reduced rate of warfarin catabolism, which is associated with a decreased dose requirement and an increased time required to achieve steady state.
      • Loading doses may be required.
      • Vulnerability to drug-drug interactions may also be increased.
    • The CYP2C cluster variant (rs12777823) is associated with a decreased dose requirement in some people of African descent but is not included in algorithms intended for other populations. The mechanism underlying the association is not well characterized, but this variant was included in Tier 2 variant recommendations from the Association of Molecular Pathology and the College of American Pathologists.
  • No variants detected: predictive of *1 functional allele
  • Genotype should be interpreted with clinical information.
  • Functional variants without clinical indication or impact on clinical management may not be reported.
  • Genetic information and nongenetic factors can be used in combination with warfarin dose calculators.
  • Additional dosing guidance is available through drug labeling and professional guidance documents, such as those published by the American College of Chest Physicians (CHEST)  and the Clinical Pharmacogenetics Implementation Consortium (CPIC). 

Limitations

  • Only the targeted genetic variants will be detected by this panel, and assumptions about phase and content are made to assign alleles.
  • 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 nongenetic factors that are not detected by this test.
  • This result does not replace the need for therapeutic drug or clinical monitoring.

References