FeedbackPolymerase Chain Reaction/Fluorescence Monitoring/Sequencing
- 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.
Polymerase Chain Reaction/Fluorescence Monitoring/Sequencing
- 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
Related Tests
Polymerase Chain Reaction/Fluorescence Monitoring
- Assesses genetic risk of abnormal drug metabolism for CYP2B6 substrates
- May aid in drug selection and dose planning
Polymerase Chain Reaction/Fluorescence Monitoring
- Assesses genetic risk of abnormal drug metabolism for CYP2C19 substrates
- May aid in drug selection and dose planning
Polymerase Chain Reaction/Fluorescence Monitoring
- Assesses genetic risk of abnormal drug metabolism for CYP2C8, CYP2C9, and/or CYP2C cluster substrates
- May aid in drug selection and dose planning
Polymerase Chain Reaction/Fluorescence Monitoring/Sequencing
- Assesses genetic risk of abnormal drug metabolism for CYP2D6 substrates
- Includes detection of common copy number variations and gene hybrids
- To better predict metabolic phenotype, testing to further characterize gene duplication(s) may be performed.
- May aid in drug selection and dose planning
Polymerase Chain Reaction/Fluorescence Monitoring
- Assesses genetic risk of abnormal drug metabolism for substrates of CYP3A4 and/or CYP3A5
- May aid in drug selection and dose planning
Polymerase Chain Reaction/Fluorescence Monitoring
Use to identify individuals with inherited variants that affect metabolism (CYP2C9) and/or sensitivity (CYP4F2, VKORC1) to warfarin
The cytochrome P450 (CYP) isozymes 2B6, 2C19, 2C8, 2C9, 2D6, 3A4, and 3A5 are involved in the metabolism of many drugs. Variants in the genes that code for these enzymes may influence pharmacokinetics of the respective medications, and therefore may predict or explain nonstandard dose requirements, therapeutic failure, or adverse reactions.
Disease Overview
Treatment Issues
- The actual metabolic phenotype of a drug metabolizing enzyme is subject to drug-drug interactions, clinical factors, and other nongenetic factors.
- Therapeutic drug monitoring and/or metabolic ratios may be useful for evaluating the pharmacokinetics of a particular drug for a particular patient.
- See the ARUP Laboratory Test Directory (www.aruplab.com/) for a list of available drug-gene specific testing (search by test name or number).
- The Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Food and Drug Administration (FDA) have published clinical associations and dosing guidelines involving CYP genotypes. Refer to the following list for specific dosing guidelines:
- Atomoxetine (eg, Strattera)
- Clopidogrel (eg, Plavix)
- Efavirenz
- Opioids (eg, codeine , tramadol)
- Siponimod (eg, Mayzent )
- Nonsteroidal anti-inflammatory drugs (NSAIDs)
- Ondansetron and Tropisetron
- Phenytoin (eg, Dilantin)
- Proton pump inhibitors (eg, omeprazole)
- Selective serotonin reuptake inhibitors (eg, citalopram)
- Tacrolimus (eg, Prograf)
- Tamoxifen
- Tricyclic antidepressants (eg, amitriptyline)
- Voriconazole
- Warfarin (eg, Coumadin)
Genetics
Genes
CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2C rs12777823, CYP2D6, CYP3A4, CYP3A5
Inheritance
Autosomal codominant
Variants Tested
Variants or groups of variants are classified as “star” (*) alleles, that are associated with predicted enzyme function, 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 PharmVar or PharmGKB.
|
Gene (Transcript) |
Alleles |
Predicted Allele Function |
|---|---|---|
| CYP2B6 (NM_000767) | CYP2B6*4: rs2279343, c.785A>G | Increased function |
| CYP2B6*6: rs3745274, c.516G>T; rs2279343, c.785A>G |
Decreased function |
|
| CYP2B6*7: rs3745274, c.516G>T; rs2279343, c.785A>G; rs3211371, c.1459C>T | Decreased function | |
| CYP2B6*9: rs3745274, c.516G>T | Decreased function | |
| CYP2B6*18: rs28399499, c.983T>C | No function | |
| CYP2B6*22: rs34223104, c.-82T>C | Increased function | |
| CYP2B6*36: rs34223104, c.-82T>C; rs3745274, c.516G>T; rs2279343, c.785A>G | Decreased function | |
| CYP2C19 (NM_000769) |
CYP2C19*2: rs4244285, c.681G>A; rs12769205, c.332-23A>G |
No function |
|
CYP2C19*3: rs4986893, c.636G>A |
No function |
|
|
CYP2C19*4A: rs28399504, c.1A>G |
No function |
|
| CYP2C19*4B: rs12248560, c.-806C>T; rs28399504, c.1A>G | No function | |
|
CYP2C19*5: rs56337013, c.1297C>T |
No function |
|
|
CYP2C19*6: rs72552267, c.395G>A |
No function |
|
|
CYP2C19*7: rs72558186, c.819+2T>A |
No function |
|
|
CYP2C19*8: rs41291556, c.358T>C |
No function |
|
|
CYP2C19*9: rs17884712, c.431G>A |
Decreased function |
|
|
CYP2C19*17: rs12248560, c.-806C>T |
Increased function |
|
|
CYP2C19*35: rs12769205, c.332-23A>G |
No function |
|
| CYP2C8 (NM_000770) |
CYP2C8*2: rs11572103, c.805A>T |
Decreased function |
|
CYP2C8*3: rs10509681, c.1196A>G |
Decreased function |
|
|
CYP2C8*4: rs1058930, c.792C>G |
Decreased 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 | |
| CYP2D6 (M33388 sequence) | CYP2D6*2: rs16947, g.2850C>T; rs1135840, g.4180G>C | Functional |
| CYP2D6*2A: rs1080985, g.-1584C>G; rs16947, g.2850C>T; rs1135840, g.4180G>C | Functional | |
| CYP2D6*3: rs35743686, g.2549del | No function | |
|
CYP2D6*4: rs1065852, g.100C>T; rs3892097, g.1846G>A; rs1135840, g.4180G>C |
No function |
|
|
CYP2D6*5: gene deletion |
No function |
|
|
CYP2D6*6: rs5030655, g.1707del; rs1135840, g.4180G>C |
No function |
|
|
CYP2D6*7: rs5030867, g.2935A>C |
No function |
|
|
CYP2D6*8: rs5030865, g.1758G>T; rs16947, g.2850C>T; rs1135840, g.4180G>C |
No function |
|
|
CYP2D6*9: rs5030656, g.2615_2617del |
Decreased function |
|
|
CYP2D6*10: rs1065852, g.100C>T; rs1135840, g.4180G>C |
Decreased function |
|
|
CYP2D6*11: rs1080985, g.-1584C>G; rs201377835, g.883G>C; rs16947, g.2850C>T; rs1135840, g.4180G>C |
No function |
|
|
CYP2D6*13: a CYP2D7-derived exon 1 conversion |
No function |
|
|
CYP2D6*14: rs5030865, g.1758G>A; rs16947, g.2850C>T; rs1135840, g.4180G>C |
Decreased function |
|
|
CYP2D6*15: rs774671100, g.137_138insT |
No function |
|
|
CYP2D6*17: rs28371706, g.1023C>T; rs16947, g.2850C>T; rs1135840, g.4180G>C |
Decreased function |
|
|
CYP2D6*29: rs16947, g.2850C>T; rs59421388, g.3183G>A; rs1135840, g.4180G>C |
Decreased function |
|
|
CYP2D6*35: rs1080985, g.-1584C>G; rs769258, g.31G>A; rs16947, g.2850C>T; rs1135840, g.4180G>C |
Functional |
|
|
CYP2D6*36: a CYP2D6*10 carrying a CYP2D7-derived exon 9 conversion |
No function |
|
|
CYP2D6*36-*10: a CYP2D6*36 and a CYP2D6*10 in tandem |
Decreased function |
|
| CYP2D6*40: rs28371706, g.1023C>T; rs72549356, c.1863_1864ins TTTCGCCCCTTTCGCCCC; rs16947, g.2850C>T; rs1135840, g.4180G>C | No function | |
|
CYP2D6*41: rs16947, g.2850C>T; rs28371725, g.2988G>A; rs1135840, g.4180G>C |
Decreased function |
|
| CYP2D6*42: rs16947, g.2850C>T; rs72549346, g.3260_3261insGT; rs1135840, g.4180G>C | No function | |
|
CYP2D6*49: rs1065852, g.100C>T; rs1135822, g.1611T>A; rs1135840, g.4180G>C |
Decreased function |
|
|
CYP2D6*69: rs1065852, g.100C>T; rs16947, g.2850C>T; rs28371725, g.2988G>A; rs1135840, g4180G>C |
No function |
|
|
CYP2D6*114: rs1065852, g.100C>T; rs5030865, g.1758G>A; rs16947, g.2850C>T; rs1135840, g.4180G>C |
No function |
|
|
DUP: complete gene duplication |
Varies based on the allele that is duplicated |
|
| CYP3A4 (NM_017460) |
CYP3A4*1B: rs2740574, c.-392G>A |
Normal function |
|
CYP3A4*15: rs4986907, c.485G>A |
Decreased function |
|
|
CYP3A4*22: rs35599367, c.522-191C>T |
Decreased function |
|
| CYP3A5 (NM_000777) |
CYP3A5*3: rs776746, c.219-237A>G |
No function |
|
CYP3A5*6: rs10264272, c.624G>A |
No function |
|
|
CYP3A5*7: rs41303343, c.1035dup |
No function |
|
|
aThe CYP2C cluster variant is associated with a decreased warfarin dose requirement in some people of African descent. |
||
Results
- Genetic variant(s) detected: alleles detected are reported. The combination of alleles detected or diplotype is used to predict metabolizer phenotype, and in the case of CYP2D6, the activity score. Phenotype predictions are subject to change as the scientific and clinical evidence evolves.
- No variants detected is predictive of *1 functional alleles.
- Functional variants without clinical indication or impact on clinical management may not be reported.
Limitations
- Only the targeted genetic variants will be detected by this panel. Assumptions about phase and content are made to assign alleles.
- Diagnostic errors can occur due to rare sequence variations.
- A combination of the CYP2D6*5 (gene deletion) and a CYP2D6 gene duplication cannot be specifically identified; however, this combination is not expected to adversely affect the phenotype prediction.
- Risk of therapeutic failure or adverse reactions with gene substrates may be affected by genetic and nongenetic factors that are not detected by this test. The test result does not replace the need for therapeutic drug or clinical monitoring.
- The test result does not replace the need for therapeutic drug or clinical monitoring.
References
-
CPIC Guidelines
Clinical Pharmacogenetics Implementation Consortium. CPIC guidelines. [Updated: Mar 2021; Accessed: Oct 2021]
-
FDA - Table of pharmacogenetic associations
U.S. Department of Health and Human Services, Food and Drug Administration. Table of pharmacogenetic associations. [Updated: Feb 2020; Accessed: Dec 2020]
-
CPIC Guideline for atomoxetine based on CYP2D6 genotype
Clinical Pharmacogenetics Implementation Consortium. Guideline for atomoxetine based on CYP2D6 genotype. [Updated: Oct 2019; Accessed: Dec 2020]
-
CPIC Guideline for Clopidogrel and CYP2C19
Clinical Pharmacogenetics Implementation Consortium. CPIC guideline for clopidogrel and CYP2C19. [Updated: Mar 2017; Accessed: Dec 2020]
-
CPIC guideline for Efavirenz
Clinical Pharmacogenetics Implementation Consortium. CPIC guideline for Efavirenz based on CYP2B6 genotype. [Accessed: Jan 2022]
-
CPIC Guideline for Codeine and CYP2D6
Clinical Pharmacogenetics Implementation Consortium. CPIC guideline for codeine and CYP2D6. [Updated: Oct 2019; Accessed: Dec 2020]
-
USFDA - Mayzent package insert
U.S. Food and Drug Administration. Mayzent package insert. [Revised: Mar 2019; Accessed: Dec 2020]
-
CPIC Guideline for NSAIDs based on CYP2C9 genotype
Clinical Pharmacogenetics Implementation Consortium. CPIC guideline for NSAIDs based on CYP2C9 genotype. [Updated: Mar 2020; Accessed: Dec 2020]
-
CPIC Guideline for Ondansetron and Tropisetron
Clinical Pharmacogenetics Implementation Consortium. CPIC Guideline for ondansetron and tropisetron based on CYP2D6 genotype. [Last modified: Oct 2019; Accessed: Dec 2020]
-
CPIC Guideline for Phenytoin and CYP2C9 and HLA-B
Clinical Pharmacogenetics Implementation Consortium. CPIC guideline for phenytoin and CYP2C9 and HLA-B. [Updated: Aug 2020; Accessed: Dec 2020]
-
CPIC guideline for proton pump inhibitors and CYP2C19
Clinical Pharmacogenetics Implementation Consortium. CPIC guideline for proton pump inhibitors and CYP2C19. [Last modified: Aug 2020; Accessed: Dec 2020]
-
CPIC Guideline for Selective Serotonin Reuptake Inhibitors
Clinical Pharmacogenetics Implementation Consortium. CPIC guideline for selective serotonin reuptake inhibitors and CYP2D6 and CYP2C19. [Updated: Oct 2019; Accessed: Dec 2020]
-
CPIC Guideline for Tacrolimus and CYP3A5
Clinical Pharmacogenetics Implementation Consortium. CPIC guideline for tacrolimus and CYP3A5. [Last modified: Jul 2015; Accessed: Dec 2020]
-
CPIC Guideline for Tamoxifen
Clinical Pharmacogenetics Implementation Consortium. CPIC guideline for tamoxifen based on CYP2D6 genotype. [Last modified: Oct 2019; Accessed: Dec 2020]
-
CPIC Guideline for Tricyclic Antidepressants
Clinical Pharmacogenetics Implementation Consortium. CPIC guideline for tricyclic antidepressants and CYP2D6 and CYP2C19. [Updated: Oct 2019; Accessed: Dec 2020]
-
CPIC Guideline for Voriconazole and CYP2C19
Clinical Pharmacogenetics Implementation Consortium. CPIC guideline for voriconazole and CYP2C19. [Last modified: Dec 2016; Accessed: Dec 2020]
-
CPIC Guideline for Pharmacogenetics-Guided Warfarin Dosing
Clinical Pharmacogenetics Implementation Consortium. CPIC guideline for pharmacogenetics-guided warfarin dosing. [Last modified: Apr 2019; Accessed: Apr 2019]
-
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Whirl-Carrillo M, McDonagh EM, Hebert JM, et al. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012;92(4):414-417.