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

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

See Variants Tested table for more information

Related Tests

Use to assess genetic risk of abnormal drug metabolism for CYP2C8, CYP2C9, and/or CYP2C cluster substrates

  • Assesses genetic variants contributing to risk of abnormal drug metabolism for drugs metabolized by enzymes coded by CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, 2C cluster variant (rs12777823), CYP3A4, and CYP3A5
  • May aid in drug selection and dose planning for many drugs that are either activated or inactivated by one or more CYP450 enzymes; recommendations may include drug avoidance or nonstandard dosing
  • Assesses genetic variants contributing to risk of abnormal drug metabolism for drugs metabolized by enzymes coded by CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, 2C cluster variant (rs12777823), CYP3A4, and CYP3A5
  • May aid in drug selection and dose planning for many drugs that are either activated or inactivated by one or more CYP450 enzymes; recommendations may include drug avoidance or nonstandard dosing
  • Report may include comprehensive medication guidance based on the genotypes detected and access to GeneDose Live, a cloud-based medication management and risk mitigation tool.

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 is administered as a racemic mixture; s-warfarin is more potent than r-warfarin and is thought to mediate most of the anticoagulant activity of warfarin.
  • 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
  • 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 ~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).
    • ~1% of individuals die due to bleeding complications associated with warfarin.
    • ~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  www.pharmvar.org or www.pharmgkb.org.

Gene (Transcript) Alleles Predicted Allele Function

CYP2C cluster (NC_000010)

CYP2C: rs12777823, g.96405502 G>A

Unclassifieda

CYP2C9 (NM_000771)

CYP2C9*2: rs1799853, c.430C>T

Decreased function

CYP2C9*3: rs1057910, c.1075A>C

Decreased function

CYP2C9*4: rs56165452, c.1076T>C

Decreased function

CYP2C9*5: rs28371686, c.1080C>G

Decreased function

CYP2C9*6: rs9332131, c.818del

No function

CYP2C9*8: rs7900194, c.449G>A

Decreased function

CYP2C9*11: rs28371685, c.1003C>T

Decreased function

CYP2C9*12: rs9332239, c.1465C>T

Decreased function

CYP4F2 (NM_001082)

CYP4F2*3: rs2108622, c.1297G>A (c.1275G>A b)

Unclassifiedc

VKORC1 (NM_024006)

VKORC1*2: rs9923231, c.-1639G>A

Warfarin 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.

Test Interpretation

Sensitivity/Specificity

  • Clinical sensitivity: genetic factors and known non-genetic factors account for ~50% of the variability in warfarin dose 
  • Analytical 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, such as through www.WarfarinDosing.org.
  • 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