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Test Catalog

Test ID: 3A4V    
Cytochrome P450 3A4 Genotype, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Aids in determining therapeutic strategies for drugs that are metabolized by CYP3A4, including atorvastatin, simvastatin, and lovastatin

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

CYP3A4 is a member of the CYP3A family of genes located on chromosome 7. The CYP3A subfamily of enzymes is responsible for the metabolism of more than 50% of medications that undergo hepatic metabolism and first-pass metabolism in intestinal epithelial cells, including some lipid-lowering drugs. The CYP3A4 enzyme activity is highly variable. Interindividual differences in enzyme expression may be due to several factors including: variable homeostatic control mechanisms, disease states that alter homeostasis, up- or down-regulation by environmental stimuli, and genetic variation.(1) It should also be noted that most drugs metabolized by CYP3A4 are also metabolized by CYP3A5, but usually to a lesser extent, so testing of CYP3A5 may also be relevant and should be determined on a case by case basis. If CYP3A5 genotyping is needed, order 3A5V / CYP3A5 Genotype.

 

One variant, CYP3A4*22 (c.522-191C>T), has been studied extensively. This variant affects hepatic expression of CYP3A4 and response to statin drugs. The CYP3A4*22 allele is associated with reduced CYP3A4 activity, which may result in a better response to lipid-lowering drugs, such as simvastatin, atorvastatin, or lovastatin. However, reduced CYP3A4 activity may also be associated with statin-induced myopathy, especially for simvastatin. Studies show that in livers with the wild-type genotype (homozygous C or CC) the CYP3A4 mRNA level and enzyme activity were 1.7- and 2.5-fold greater than in heterozygous CYP3A4*22 (CT) and homozygous CYP3A4*22 (TT) carriers, respectively. In 235 patients taking stable doses of drugs for lipid control, carriers of the T allele required significantly lower statin doses for optimal lipid control than did non-T carriers.(2) These results indicate that CYP3A4*22 markedly affects expression of CYP3A4 and could serve as a biomarker for CYP3A4 metabolizer phenotype. The reported allele frequency of CYP3A4*22 is 5% to 8% in Caucasians and 4.3% in African American and Chinese populations.

 

Other alleles have not been as extensively studied in clinical trials but are expected to have similar impacts on statin metabolism and the metabolism of other drugs primarily metabolized by CYP3A4.

 

The following table displays the CYP3A4 variants detected by this assay, the corresponding star allele, and the effect on CYP3A4 enzyme activity. Individuals without a detectable CYP3A4 variant are designated as CYP3A4*1/*1.

CYP3A4 Allele

cDNA Nucleotide Change

Effect on Enzyme Activity

*1

None (wild type)

Normal activity

*8

389G->A

No activity

*11

1088C->T

Reduced activity

*12

1117C->T

Reduced activity

*13

1247C->T

No activity

*16

554C->G

Minimal activity

*17

566T->C

No activity

*18

878T->C

Reduced activity

*22

522-191C->T

Reduced activity

*26

802C->T

No activity

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided.

 

The genotype, with associated star alleles, is assigned using standard allelic nomenclature as published by the Pharmacogene Variation (PharmVar) Consortium.(3)

 

For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomics Associations Tables in Special Instructions. This resource also includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Rare variants may be present that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing could be considered.

 

Samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic blood or marrow transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient's genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. For individuals who have received allogeneic blood or marrow transplantation, a pretransplant DNA specimen is recommended for testing.

 

CYP3A4 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient's CYP3A4 status.

 

This test does not detect all variants that result in altered CYP3A4 activity. Therefore, absence of a detectable variant does not rule out the possibility that a patient has altered CYP3A4 metabolism due to other CYP3A4 variants that cannot be detected with this method. Furthermore, when 2 or more variants are identified, the cis-/trans- status (whether the variants are on the same or opposite chromosomes) is not always known.

 

Drug-drug interactions and drug-metabolite inhibition must be considered.

 

Drug-metabolite inhibition can occur, resulting in inhibition of CYP3A4 catalytic activity.

 

Patients may also develop toxicity problems if liver and kidney function are impaired.

 

CYP3A4 genotyping should not be ordered for managing patients receiving fluvastatin, rosuvastatin, or pravastatin since these drugs are not metabolized appreciably by CYP3A4.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Evans WE, Relling RV: Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999;486:487-491

2. Wang D, Guo Y, Wrighton SA, et al: Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J 2011;11:274-286

3. Pharmacogene Variation Consortium database. Accessed 04/27/2018. Available at https://www.pharmvar.org/gene/CYP3A4

4. Lamba JK, Lin YS, Schuetz EG, Thummel KE: Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 2002;18:1271-1294

5. Elens L, Becker ML, Haufroid V, et al: Novel CYP3A4 intron 6 single nucleotide polymorphism is associated with simvastatin-mediated cholesterol reduction in the Rotterdam study. Pharmacogenet Genomics 2011;21(12):861-866

6. Elens L, Van Schaik RH, Panin N, et al: Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitor' dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenomics 2011;12(10):1383-1396

7. Clinical Pharmacogenetic Implementation Committee Gene-Drug Table. Accessed 5/3/2017. Available at https://cpicpgx.org/genes-drugs/

Special Instructions Library of PDFs including pertinent information and forms related to the test