The Genetics of Warfarin Response
What is warfarin?
Warfarin, also known as Coumadin®, is a medication that is used to
prevent blood from clotting, also known as an anticoagulant. Blood clots can block
the flow of blood through the body. If blood flow is blocked it can lead to tissue
or organ damage.
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Warfarin is prescribed for any of the following reasons:
- To prevent and/or treat blood clots that form in veins or that get stuck in the
lungs (also called a pulmonary embolism)
- To reduce the risk of blood clots in people who have:
- An abnormal heart rhythm (also called atrial fibrillation)
- had a heart valve replaced
- had a heart attack
- To reduce the risk of death, recurrent heart attacks, and stroke after a heart attack
In 2002, over 3 million patients in the U.S. were taking warfarin1.
Warfarin is the drug warfarin sodium. Coumadin® is the most
common brand name for warfarin. Other brand names include Jantoven®
and Marfarin®.
Warfarin works by interfering with the production of vitamin K and other proteins
required for blood clotting. When warfarin interferes with the production of vitamin
K, the body cannot make as many blood clotting proteins. With less blood clotting
proteins, the ability of the blood to clot is reduced.
Why might different people require different warfarin doses?
Several factors influence the dose of warfarin needed to prevent blood clots without
causing dangerous side effects. Genetic variation explains up to 40% of the differences
between individuals. The remaining 60% of the variation in warfarin response can
be explained by non-genetic factors, including age, weight, gender, race, diet,
other medications and smoking status2.
If only genetic variation is taken into account, then in a Caucasian population:
- 65 out of a 100 are likely to need a higher dose
of warfarin (4.5 mg per day or more)
- 32 out of a 100 are likely to need an intermediate
dose of warfarin (2.6 to 4.4 mg per day)
- 3 out of 100 are likely to need a lower dose of
warfarin (2.5 mg per day or less)

Which genes affect warfarin dose requirements?
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Some of the variability between individuals in warfarin dosing requirements is due
to genetics. VKORC1, CYP2C9, and CYP4F2 are the genes that affect warfarin response
the most. The CPMC analyzes these three genes to determine whether you may need
a higher, lower or intermediate dose of warfarin. This information may be useful
should your doctor prescribe warfarin for you in the future or if you are on warfarin
and the best dose for you has not yet been determined.
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The human body uses vitamin K in the blood clotting process. If vitamin K recycling
is less efficient, then a person’s blood will not clot as easily. The VKORC1 gene
codes for an enzyme that helps with the recycling of vitamin K. Genetic variation
in VKORC1 can reduce the ability of this enzyme to recycle vitamin K. If the ability
of the blood to clot is reduced, then a lower dose of warfarin may be needed. Higher
doses of warfarin could be dangerous, because too much warfarin could slow clotting
to the point where bleeding cannot stop.
The "A" variant (rs9923231) of the VKORC1 gene causes less efficient vitamin K recycling.
This variant is responsible for 10% to 30% of the variability in warfarin response3.
The CYP2C9 gene helps your body break down warfarin. There are several variants
in the CYP2C9 gene that can cause the CYP2C9 enzyme to be less active. When the
CYP2C9 enzyme is less active, warfarin stays in the body for a longer period of
time. This means that lower warfarin doses
are needed in people with certain (reduced function) CYP2C9 genetic variants. Variation
in the CYP2C9 gene is responsible for up to 18% of variability in warfarin response3.
For CYP2C9 and many other genes involved in drug response, there are multiple genetic
variants that impact the way the body responds to a drug.
Your response to warfarin is determined by your specific combination of genetic
variants, not simply by the number of variants that you have. Each combination of
genetic variants in or near a gene is called a “haplotype”. There can be many different
combinations of variants for each gene. To distinguish one combination of variants
from another, scientists sometimes use a numbering system. For example: one combination
of variants within the CYP2C9 gene may be called “star 2”, written as *2, while
another combination is *1.

Since we have two copies of each gene, one inherited from our mother and one from
our father, each person will have a combination of variants (called a haplotype)
from each parent. When genetic testing is performed for CYP2C9 the results are noted
as two numbers (one representing each haplotype or combination of variants in that
gene), separated by a slash. For example, someone who inherited the combination
of variants from their mother known as *2 and the combination known as *3 from their
father would be a *2/*3 for the gene tested. Some people have combinations of variants
that are rare and have not been studied or named. Sometimes, the specific genetic
test performed cannot determine a person’s result with certainty due to these rare
and/or unnamed variants.

Different combinations of variants (called a haplotype) in the CYP2C9 gene can be
used to predict how a person will respond to warfarin. A person’s predicted response
is based on the two CYP2C9 haplotypes that a person inherited from his or her parents.
CYP2C9 Gene Variants Detected by the CPMC
Variant
Tested
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Variant
Name
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Reference
Valuea
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Variant
Value
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rs1799853
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CYP2C9*2
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C
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T
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rs1057910
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CYP2C9*3
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A
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C
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rs28371686
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CYP2C9*5
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C
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G
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rs9332131b
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CYP2C9*6
|
A
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-
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rs28371685
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CYP2C9*11
|
C
|
T
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rs72558189
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CYP2C9*14
|
G
|
A
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a If the laboratory finds the reference value present for each of the
variant sites tested this will indicate no variants are present (commonly called
CYP2C9*1)
b This variant is a deletion variant where the reference value is the
presence of an “A” and the variant value is a deletion of the A denoted by a minus
sign "-"
In addition to warfarin, your genetic results for CYP2C9 can affect your response
to other drugs. Different drugs can be processed in different ways by the body.
Because of these differences, the gene variants you carry do not always predict
the same response for all drugs, even when those drugs are metabolized by that same
gene.
Examples:
- CYP2C9 metabolizes phenytoin (an anti-seizure drug). The same variant in CYP2C9
that causes someone to need a lower dose of warfarin may also cause that same individual
to need a lower dose of phenytoin.
- CYP2C9 metabolizes losartan (a drug that treats high blood pressure). The same variant
in CYP2C9 that causes someone to need a lower dose of warfarin may cause that same
individual to need a higher dose of losartan.
The CYP4F2 gene also plays a role in helping the body use vitamin K in the blood
clotting process. CYP4F2 helps to reduce blood clotting by decreasing the amount
of vitamin K.
People with the "A" variant in the CYP4F2 gene could have increased vitamin K levels
and may therefore need a higher warfarin dose to prevent clotting.
Differences in CYP4F2 genotype account for approximately 1-7% of the variability
in warfarin response between individuals4,5.
In some cases, the expected response to warfarin is not known and cannot be predicted.
In some cases, genetic testing provides enough information to determine the general
response category (e.g. reduced or intermediate dose may be required) but more specific
guidance cannot be given. There is a chance that gene variants that have not been
tested can affect warfarin response. This can reduce the accuracy of the predicted
warfarin dose level needed (intermediate, higher or lower). It is also possible
that technical limitations encountered during genetic testing could prevent prediction
of whether you will need a higher, lower or intermediate dose of warfarin.
Are there other factors that can affect how warfarin works?
Many factors affect how your body will respond to a medication. Non-genetic factors
include interactions between different drugs you may be taking, other medical conditions
you may have, and interactions between drugs and your lifestyle (diet, exercise,
smoking, alcohol consumption etc.).
There are over 100 medications that, when taken with warfarin,
can cause an increase in the effect of warfarin and may result in increased
risk for bleeding.
There are over 40 medications that, when taken with warfarin, can
cause a decrease in the effect of warfarin and may result in an increased risk
for blood clots.
For a list of medications that may affect your response to warfarin, click here.
It is important that you talk to your healthcare providers about all of the medications
(both over-the-counter and prescription) as well as supplements that you are taking,
as they may interact with warfarin. Do NOT make any changes to ANY medications
without talking to your healthcare providers.
The following foods are known to interact with warfarin:
- Cruciferous vegetables (e.g., broccoli, kale, cabbage, Brussels sprouts etc.), which
contain high levels of vitamin K
- Garlic
- Cranberry
For a list of more foods, vitamins, and supplements that may affect your response
to warfarin,
click here.
If you are taking warfarin now, or are prescribed it in the future, talk to your
healthcare providers about foods, vitamins and supplements that may interact with
warfarin.
Talk to your healthcare providers about all of the medications (both over the counter
and prescription) as well as any supplements that you are taking.
What does the CPMC Test?
The CPMC evaluates 8 variants associated with warfarin response: 6 variants in the
CYP2C9 gene, 1 in the VKORC1 gene, and 1 in the CYP4F2 gene. Your personal result
will be displayed in the form of a table on the YOUR GENETIC RESULT tab within your
personal report. Your result interpretation can be found on a separate YOUR RESULT
INTERPRETATION tab.
As you can see from the sample results table below, each
variant tested is listed by its "rs number", the number used by scientists to name
genetic variants. In the next column of the table you will find the reference value.
The reference value shows the result for someone who is expected to break down warfarin
at the normal or 'typical' rate. Because we have two copies of every gene, one from
mom and one from dad, everyone tested will have two results, represented by letters
(example: CT) for each variant tested. In the third column, we display your results.
Since it is your personal combination of variants that is important in interpreting
your results, you will be provided with your combined genetic results in the far
right column.
SAMPLE REPORT:

In addition to the YOUR GENETIC RESULTS tab, which will show your personal result
for each variant tested, you will be provided with an interpretation (found on the
YOUR RESULT INTERPRETATION tab). The interpretation will give you information about
how your personal result will impact your predicted warfarin dose. In some cases
this information will not be known.
SAMPLE REPORT:

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It is important to note that CPMC testing alone cannot fully predict your response
to warfarin or any other drug. Other factors like body weight, other health conditions,
and other medications may also influence the way a person will respond to warfarin
and other drugs. It is possible that you may have other genetic variants that occur
in the VKORC1, CYP2C9, and/or CYP4F2 genes that are not tested by the CPMC. Also,
it is possible that you may have variants in other genes that influence your response
to warfarin.
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For More Information?
- PubMed
Health Summary of Warfarin
- Drugs@FDA Warfarin Drug Details
- Drugs.com
- Warfarin
References
- Kaufman DW, Kelly JP, Rosenberg L, et al. J Am Med Assoc. 2002;287:337–344.
- Cavallari LH & Limdi, NA. Curr Opin Mol Ther. 2009 Jun;11(3):243-51.
- Johnson JA, et al. Clin Pharmacol Ther. 2011:(4):625-9.
- Pautas E, et al.Clin Pharmacol Ther. 2010 Jan;87(1):57-64.
- Borgiani P, et al. Pharmacogenomics. 2009 Feb;10(2):261-6.
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