|
Frequently asked questions
What is PGxPredict™:WARFARIN test?
The PGxPredict:WARFARIN test is a genetic test. It assays 2 genes, CYP2C9 and VKORC1 for variation that may affect how patients respond to warfarin.
What is CYP2C9?
CYP2C9 is a member of the cytochrome p450 superfamily of enzymes, which catalyze the metabolism of xenobiotics or foreign substances, including drugs. Drugs may be metabolized by 0, 1, or >1 enzyme in the cytochrome P450 system. The enzymes are named as members of families (of which there are 3) and subfamilies. CYP2C9 is enzyme number 9 in family 2, subfamily C. Traditionally, patients are classified according to the metabolizing ability of the enzyme as an Extensive, Intermediate, or Poor Metabolizer.
What are *1, *2, and *3?
The CYP2C9 gene has two common variants that result in reduced enzymatic function: *2 and *3. The PGxPredict:WARFARIN test determines the number of these variants a patient has. Since each patient has two copies of the CYP2C9 gene, a patient can have 0, 1 or 2 reduced function copies with the other copies most likely to be wildtype, referred to as *1, or fully functional genes. (Other variants that account for ~5% of the CYP2C9 poor metabolizer phenotype are not measured in this test.) The
PGxPredict:WARFARIN test thus predicts CYP2C9 metabolizer status according to the following table:
| *2 Allele Count
| *3 Allele Count |
Warfarin Metabolic Status |
0 |
0 |
Extensive |
1 |
0 |
Intermediate |
2 |
0 |
Poor |
0 |
1 |
Intermediate |
1 |
1 |
Poor |
0 |
2 |
Poor |
How common are the Intermediate and Poor Metabolizer phenotypes for CYP2C9?
The most common genetic contributors to intermediate or poor metabolism of warfarin are the haplotypes CYP2C9*2 and CYP2C9*3, found in ~35% of Caucasians but much less frequently in Africans and Asians. Other variants that account for ~5% of the CYP2C9 poor metabolizer phenotype are not measured in PGxPredict:WARFARIN test.
Why does this matter for treating my patients with warfarin?
Warfarin consists of 2 two active enantiomers, R and S. The S-enantiomer, which is the more potent of the two, is metabolized to an inactive form by CYP2C9. Therefore, if a person has reduced CYP2C9 function, the effective blood level of warfarin may be increased and they may require a lower dose of warfarin than an Extensive Metabolizer.ii
What about other drugs that affect CYP2C9 activity?
Some drugs may turn on (induce) or turn off (inhibit) CYP2C9 activity. Yet other drugs (substrates) may reduce CYP2C9’s action on warfarin by competing for its use. If any of these drugs are prescribed in combination with warfarin, they may increase or decrease the metabolism of warfarin and require a dose adjustment. You should consider consultation with a clinical pharmacologist if it is necessary to co-prescribe any CYP2C9 inhibitors, inducers, or substrates with warfarin.
Can I order CYP2C9 genotypes as a separate test?
No; currently, this test must be ordered with VKORC1 testing as described elsewhere.
What is VKORC1?
VKORCI is the name of the gene that encodes subunit 1 of the target protein of warfarin, the Vitamin K epoxide reductase complex. It catalyzes the reduction of Vitamin K, which in turn leads to the production of the activated Vitamin K dependent clotting factors, Factors II, VII, IX, and X.
What is VKORC1 -1639G>A?
This denotes a variable position in the VKORC1 gene that is 1639 bases upstream from the ‘start’ codon of the gene. This variant has been associated with altered sensitivity of the enzyme to warfarin and, therefore, with the dose of warfarin needed to achieve and maintain a therapeutic INR. The most common nucleotide at this position in Caucasians and Africans is G, or guanine; the variant nucleotide associated with increased sensitivity is A, or adenosine. PGxPredict:WARFARIN test thus predicts warfarin sensitivity according to the following tableiii:
-1639G>A Genotype |
Warfarin Sensitivity |
GG |
Low |
GA |
Intermediate |
AA |
High |
How common is altered sensitivity of the warfarin target VKORC1?
The frequency of the intermediate and high sensitivity genotypes are roughly 47% and 14%, respectively, in Caucasians, 25% and 0% in African Americans, and 18% and 82% in Asians; other variants that account for <5% of warfarin sensitivity are not measured.iv
Why does this matter for treating my patient with warfarin?
Patients who are expected to have intermediate or high sensitivity to warfarin based on VKORC1 genotyping may require a decreased dose of warfarin.
Can I order VKORC1 genotypes as a separate test?
No; currently, this test must be ordered with CYP2C9 testing as described elsewhere.
If this test is performed, does that mean there is no need to measure prothrombin times (PT) or INRs anymore?
No it does not. The use of this test does not eliminate the need for monitoring of prothrombin times as clinically indicated. It remains just as important to insure the correct dose of warfarin is being administered based on the target PT or INR.
What dose should I put my patient on based on the test results?
We cannot make specific dosing recommendations.
I need these results before I start to treat my patient. Why is the turnaround time so long?
Because the results of this test address the maintenance dose of warfarin, you should consider introduction of warfarin treatment according to your usual practice or algorithms. The results of this test will then help you select the maintenance dose. If you have special turnaround requirements, please call
1-888-5-WARFARIN.
What specimen is required?
The PGxPredict:WARFARIN test requires a fingerstick to collect a small sample of blood on a Whatman FTA® card.
How long will it take to get test results?
Once the analysis begins, test results should be available in 3-5 days. They will be sent directly to the ordering healthcare provider.
Where is the test available?
The PGxPredict:WARFARIN test is available in all states except New York, California and Florida, where licensure is pending.
Will insurance pay for the test?
PGxHealth provides a service to help determine if insurance carriers will cover all or a portion of the cost of the test. PGxHealth will make every effort to collect payment from insurance companies. It is important to remember that the patient is responsible for the entire cost of the test.
References
i Kirchheiner, J., and Brockmoller J (2005). Clinical pharmacology and therapeutics 77:1-16
ii Sanderson et al (2005). Genetics in Medicine 7; 9
iii Rieder M et al. (2005). New Engl J Med 352;22
iv Yuan, H., et al (2005). Human molecular genetics, 14 (1745-1751) and http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=9923231
1-877-2-PGXHEALTH (877-274-9432)
|
