Warfarin Therapy and the Genotypes CYP2C9
and VKORC1
Laura Dean, MD
1
Created: March 8, 2012; Updated: June 8, 2016.
Introduction
Warfarin is an anticoagulant that acts by reducing the activity of vitamin K-dependent
clotting factors. It is used in the prevention and treatment of thrombotic disorders. e
dose of warfarin must be tailored for each patient according to the patient’s INR response
and the condition being treated.
A patient’s CYP2C9 and VKORC1 genotype can be used to help determine the optimal
starting dose of warfarin. e CYP2C9 gene encodes one of the main enzymes involved in
the metabolism of warfarin. Several variant
CYP2C9 alleles are associated with reduced
enzyme activity and lower clearance rates of warfarin. Patients who carry at least one copy
of such a variant allele (such as
CYP2C9*2 and CYP2C9*3) have reduced metabolism
leading to higher warfarin concentrations. On average, they require a lower daily warfarin
dose than patients who are homozygous for the wild-type CYP2C9*1 allele.
e VKORC1 gene encodes the vitamin K epoxide reductase enzyme, the target of
warfarin. Patients who carry the -1639G>A polymorphism in the promoter region of the
VKORC1 gene are more sensitive to warfarin and require lower doses.
e FDA-approved warfarin drug label provides a dosing table based on CYP2C9 and
VKORC1 genotypes (Table 1). e label states if the patient’s CYP2C9 and/or VKORC1
genotype are known, to consider these ranges in choosing the initial doses, but whether
this strategy reduces warfarin-related adverse events is controversial. e label also states
that patients with
CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more time (longer
than 2 to 4 weeks) to achieve maximum INR eect for a given dosage regimen than
patients without these CYP variants (
1).
1
NCBI; Email: [email protected].
NLM Citation: Dean L. Warfarin Therapy and the Genotypes CYP2C9 and VKORC1. 2012 Mar 8
[Updated 2016 Jun 8]. In: Pratt V, McLeod H, Dean L, et al., editors. Medical Genetics Summaries
[Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012-.
All Medical Genetics Summaries content, except where otherwise noted, is licensed under a
Creative Commons Attribution 4.0 International (CC BY 4.0) license which permits copying,
distribution, and adaptation of the work, provided the original work is properly cited and any
changes from the original work are properly indicated. Any altered, transformed, or adapted
form of the work may only be distributed under the same or similar license to this one.
However, the Clinical Pharmacogenetics Implementation Consortium (CPIC)
recommends that this dosing table should only be used when electronic access is not
possible. Instead, CPIC recommends that whenever possible, the pharmacogenetic
algorithms available on http://www.warfarindosing.org should be used to predict the
optimal warfarin dose (2). Although one randomized trial found that genotype-guided
dosing might improve INR control aer warfarin initiation (
3), the largest completed trial
found no benet. (4). e largest trial of pharmacogenetic dosing of warfarin
(ClinicalTrials.gov Identier: NCT01006733) is expected to have results in December
2016.
Table 1. ree Ranges of Expected Maintenance Warfarin Doses based on CYP2C9 and VKORC1
Genotypes, adapted from the FDA drug label.
VKORC1 CYP2C9
*1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3
GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg
AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg
AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg
Ranges are derived from multiple published clinical studies. VKORC1 –1639G>A (rs9923231) variant is
used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin
dose. is table is adapted from the FDA-approved drug label for Coumadin (warfarin) (1).
Drug: Warfarin
Warfarin is an anticoagulant used in the prevention and treatment of venous thrombosis,
pulmonary embolism, and the complications associated with atrial bril lation and/or
cardiac valve replacement. Warfarin is sometimes prescribed to reduce the risk of stroke
aer a myocardial infarction (MI).
Warfarin has no direct eect on an established thrombus. However, once a thrombus has
occurred (e.g., deep venous thrombosis), the goal of warfarin therapy is to prevent further
extension of the formed clot and to prevent secondary thromboembolic complications
that may be fatal (e.g., pulmonary embolism).
Warfarin exerts its anticoagulant eect by inhibiting the enzyme encoded by VKORC1,
which catalyzes the conversion of vitamin K epoxide to the active reduced form of
vitamin K, vitamin K hydroquinone. Vitamin K hydroquinone is an essential cofactor in
the synthesis of several clotting factors—it promotes the synthesis of γ-carboxyglutamic
acid residues in the proteins essential for biological activity. e decreased availability of
vitamin K hydroquinone leads to decreased activity of the clotting factors II, VII, IX, and
X, and the anticoagulant proteins C and S (
5).
Warfarin is administered as a racemic mixture of the R and S stereoisomers. (S)-warfarin
is two to ve times more potent than (R)-warfarin, and is mainly metabolized by
CYP2C9. (
R)-warfarin is mainly metabolized via CYP3A4, with involvement of several
other cytochrome P450 enzymes (6).
2 Medical Genetics Summaries
e initial and maintenance dosing of warfarin must be individualized for each patient.
e goal of warfarin therapy is to achieve an international normalized ratio (INR) in a
target range for the condition being treated (most commonly 2-3). is involves selecting
an initial starting dose, followed by regular testing of the INR so that the dose of warfarin
can be adjusted until the appropriate daily maintenance dose is determined. In general,
the duration of anticoagulant therapy varies by clinical indication and should be
continued until the danger of thrombosis and embolism has passed.
Selecting the initial dose of warfarin should be based on the expected maintenance dose,
having taken into account the factors known to inuence warfarin dose. Using an optimal
starting dose for an individual may reduce the time taken to reach a stable INR, and
reduce the risk of having either a high INR (with a risk of bleeding) or a low INR (with a
risk of thrombosis) (
2). Appropriate dosing of warfarin varies widely between individuals,
and not all factors responsible for the variability in warfarin dose are known or easily
quantied.
Known factors that inuence an individual’s response to the rst dose of warfarin include
clinical factors (e.g., age, race, body weight, sex, concomitant medications—including
those that compete for binding to albumin, comorbidities, diet, nutritional status) and
genetic factors (e.g.,
CYP2C9 and VKORC1 genotypes). erefore, the initial dose should
be modied to take into account these and any additional patient-specic factors that may
inuence warfarin response.
e FDA-approved drug label for warfarin suggests considering a lower initial and
maintenance dose of warfarin for elderly and/or debilitated patients, and in Asian
patients. e drug label recommends against the routine use of loading doses because this
practice may increase hemorrhagic and other complications and does not oer more
rapid protection against clot formation.
Warfarin can cause major or fatal bleeding. Bleeding is more likely to occur within the
rst month, and the risk factors include a high intensity of anticoagulation (INR greater
than 4), age greater than or equal to 65, and a history of highly variable INRs. Other
serious adverse events associated with warfarin therapy include necrosis of the skin and
other tissues, particularly when used prematurely to manage thrombosis associated with
heparin-induced thrombocytopenia (HIT).
Gene: CYP2C9
e cytochrome P450 superfamily (CYP450) is a large and diverse group of enzymes that
form the major system for metabolizing lipids, hormones, toxins, and drugs in the liver.
e
CYP450 genes are very polymorphic and can result in reduced, absent, or increased
enzyme activity.
CYP450 isozymes involved in the metabolism of warfarin include CYP2C9 and CYP3A4.
e more potent warfarin S-enantiomer is metabolized by CYP2C9 while the R-
enantiomer is metabolized by CYP1A2 and CYP3A4. e FDA-drug label for warfarin
Warfarin Therapy and the Genotypes CYP2C9 and VKORC1 3
states that drugs that inhibit or induce CYP2C9, CYP1A2, and/or CYP3A4 have the
potential to alter the eect (INR) of warfarin by altering the exposure of warfarin.
CYP2C9*1 is the wild-type allele and is associated with normal enzyme activity and the
normal metabolizer phenotype.
Two common allelic variants associated with reduced enzyme activity are CYP2C9*2
(Arg144Cys) and CYP2C9*3 (Ile359Leu). Compared to normal metabolizers, patients
who inherit one or two copies of *2 or *3 are more sensitive to warfarin—they require
lower doses and are at a greater risk of bleeding during warfarin initiation (7-10).
e frequencies of the CYP2C9 alleles vary between dierent ethnic groups (11-13). e
*2 allele is more common in Caucasian (10-20%) than Asian (1-3%) or African (0-6%)
populations (
14). e *3 allele is less common (<10% in most populations) and extremely
rare in African populations (15). In African Americans, it is likely that other CYP2C9
variants such as CYP2C9*5, *6, *8, and *11 contribute to the variability in patient response
to warfarin (
2).
Gene: VKORC1
e VKORC1 gene encodes the vitamin K epoxide reductase enzyme. It catalyzes the rate-
limiting step in vitamin K recycling, and it is the target of the drug warfarin.
A common non-coding variant, -1639G>A, is associated with an increased sensitivity to
warfarin (16). e polymorphism occurs in the promoter region of VKORC1 and is
thought to alter a transcription factor binding site, leading to lower protein expression. As
a result, patients starting warfarin therapy who are −1639A carriers require lower initial
and maintenance doses of the drug than −1639G carriers.
e −1639G>A allele frequency varies among dierent ethnic groups. It is the major allele
(around 90%) in Asian populations, and may be a contributing factor for lower warfarin
dosing requirements oen observed in patients of Asian descent. It is also common in
Caucasians (around 40%) and African Americans (around 14%) (
17-19).
Less commonly, missense mutations in VKORC1 can lead to warfarin resistance (20, 21).
Genetic Testing
VKORC1 and CYP2C9 genotypes are the most important genetic determinants
of warfarin dosing. e contribution of
VKORC1 to the variation in dose requirement is
larger (approximately 30%) than the contribution of CYP2C9 (usually less than 10%) (22).
Individuals who are most likely to benet from genetic testing are those who have yet to
start warfarin therapy. However, genotype-guided warfarin dosing is not the standard of
care in most healthcare systems, and most (but not all) recent studies have reported that,
in general, the use of genotype-guided dosing algorithms did not improve anticoagulation
control in the rst few weeks of warfarin therapy (
4, 23-27).
4 Medical Genetics Summaries
Genetic testing is available for CYP2C9 and VKORC1. e variants that are routinely
tested for are
CYP2C9*2, CYP2C9*3, and −1639G>A. ese variants are used in the FDA
table to guide therapy, and also in the International Warfarin Pharmacogenomics
Consortium (IWPC) algorithm.
Other variants that are not routinely tested for include the CYP2C9*6 and *8, alleles, the
genes
CYP4F2, EPHX1, and GGX (which all have a role in the vitamin-K cycle), and the
gene CALU (a cofactor in the VKOR complex) (2, 28). Including these additional
genotypes in an expanded dosing algorithm improves warfarin dose prediction in
African-Americans, while maintaining high performance in European-Americans (
29).
Therapeutic Recommendations based on Genotype
is section contains excerpted
1
information on gene-based dosing
recommendations. Neither this section nor other parts of this review contain the
complete recommendations from the sources.
2015 Statement from the US Food and Drug Administration (FDA):
Dosing Recommendations without Consideration of Genotype
If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of
warfarin is usually 2 to 5 mg once daily. Determine each patient’s dosing needs by close
monitoring of the INR response and consideration of the indication being treated. Typical
maintenance doses are 2 to 10 mg once daily.
Dosing Recommendations with Consideration of Genotype
Table 1 displays three ranges of expected maintenance COUMADIN doses observed in
subgroups of patients having dierent combinations of
CYP2C9 and VKORC1 gene
variants […]. If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider
these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and
*3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR eect
for a given dosage regimen than patients without these CYP variants.
Please review the complete therapeutic recommendations that are located here: (1)
2014 Statement from the Clinical Pharmacogenetics Implementation Consortium
(CPIC):
e pharmacogenetic algorithms available on http://www.warfarindosing.org
should be used whenever possible to determine the dose of warfarin required. Such
algorithms have been derived from large studies across dierent ethnic populations, and
they take into account both the genetic and non-genetic factors that inuence the
variability in warfarin response. e existence of rare genetic variants may be responsible
1
The FDA labels specic drug formulations. We have substituted the generic names for any
drug labels in this excerpt. The FDA may not have labelled all formulations containing the
generic drug.
Warfarin Therapy and the Genotypes CYP2C9 and VKORC1 5
for individuals whose warfarin dosing is not well predicted. However, overall the dosing
equations are well validated and fairly precise. Only if electronic access to a
pharmacogenetic algorithm is not possible should the table-based dosing approach be
used, which is preferable to a xed-dose approach.
Please review the complete therapeutic recommendations that are located here: (2,
30
).
Table 2. Recommended daily warfarin doses (mg/day) to achieve a therapeutic INR based on CYP2C9 and
VKORC1 genotype using the warfarin product insert approved by the US Food and Drug Administration
VKORC1:
–1639G>A
CYP2C9*1/*1 CYP2C9*1/*2 CYP2C9*1/*3 CYP2C9*2/*2 CYP2C9*2/*3 CYP2C9*3/*3
GG 5-7 5-7 3-4 3-4 3-4 0.5-2
GA 5-7 3-4 3-4 3-4 0.5-2 0.5-2
AA 3-4 3-4 0.5-2 0.5-2 0.5-2 0.5-2
Table is adapted from Johnson JA, Gong L, Whirl-Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL,
Kimmel SE, Lee MT, Pirmohamed M, Wadelius M, Klein TE, Altman RB; Clinical Pharmacogenetics
Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clinical
pharmacology and therapeutics. 2011;90(4):625–9 (2).
Nomenclature
Common
allele name
Alternative
names
HGVS reference sequence dbSNP
reference
identier for
allele location
Coding Protein
CYP2C9*2 430C>T
Arg144Cys
NM_000771.3:c.430C>T NP_000762.2:p.Arg144Cys rs1799853
CYP2C9*3 1075A>C
Ile359Leu
NM_000771.3:c.1075A>C NP_000762.2:p.Ile359Leu rs1057910
VKORC1:
-1639G>A
-1639G>A NM_024006.4:c.-1639G>A Not applicable - variant occurs
in a non-coding region
rs9923231
Guidelines for the description and nomenclature of gene variations are available from the
Human Genome Variation Society (HGVS): http://www.hgvs.org/content/guidelines
Nomenclature for Cytochrome P450 enzymes is available from the Human Cytochrome
P450 (CYP) Allele Nomenclature Database: http://www.cypalleles.ki.se/
Acknowledgments
e author would like to thank Brian F. Gage, MD, MSC, Professor of Medicine,
Washington University, St. Louis; and Sol Schulman, MD, Clinical Fellow in Medicine,
Division of Hemostasis and rombosis, Department of Medicine, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston; for reviewing this summary.
6 Medical Genetics Summaries
First edition:
e Pharmacogenomics Knowledgebase: http://www.pharmgkb.org
e Clinical Pharmacogenetics Implementation Consortium: http://www.pharmgkb.org/
page/cpic
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8 Medical Genetics Summaries
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Warfarin Therapy and the Genotypes CYP2C9 and VKORC1 9
