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.

^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 individuals^4,5.

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.

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.

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: