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Test ID: 3A5Q    
Cytochrome P450 3A5 Genotype, Varies

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

Aids in optimizing treatment with tacrolimus and other drugs metabolized by cytochrome P450 3A5

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

CYP3A5 is a member of the CYP3A family of genes located on chromosome 7. The cytochrome P450 (CYP) 3A subfamily of enzymes responsible for the metabolism of more than 50% of medications that undergo hepatic metabolism and first-pass metabolism in intestinal epithelial cells. The CYP3A5 expression level and enzymatic activity can be modulated by genetic variation. CYP3A5 allelic frequency depends upon ethnicity. For example, in individuals of European descent the most common allele is the CYP3A5*3 allele (c.219-237A>G), which results in a splicing defect and absence of enzyme activity. In individuals of African descent, the *1 allele (functional enzyme) is most common. The distribution of CYP3A5*3 allele frequencies ranges from 0.14 among sub-Saharan Africans to 0.95 in European populations.

 

CYP3A5 testing is commonly ordered for patients receiving tacrolimus. Tacrolimus is an immunosuppressive calcineurin inhibitor used in transplant recipients. Tacrolimus has a low therapeutic index with a wide range of side effects and large interindividual variability in its pharmacokinetics, particularly in the dose required to reach target trough blood concentrations, thus necessitating routine therapeutic drug monitoring in clinical practice.

 

Tacrolimus dose requirements are most closely associated with CYP3A5 genotype even though the drug is metabolized by both CYP3A4 and CYP3A5. According to existing literature and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, individuals with at least one copy of fully functional CYP3A5 (ie, *1/*1 and *1/*3) require a higher dose of tacrolimus to reach the targeted whole blood concentrations than those without a copy of a fully functional CYP3A5 allele (ie, *3/*3) (2-5). CYP3A5 genotyping may predict dose requirements for tacrolimus but does not replace the need for therapeutic monitoring to guide tacrolimus dose adjustments. For a patient with the CYP3A5*3/*3 genotype, initiating tacrolimus therapy with a standard (normal) dose is recommended. One of the complications in interpreting CYP3A5 genotyping results and the effect of genotype on drug dosing is the fact that most individuals involved in drug trials have been of European decent. Individuals of European decent are more likely to have the CYP3A5*3/*3 genotype, which predicts a poor metabolizer phenotype. Dosing requirements were derived from these clinical trials so individuals with 1 or 2 copies of CYP3A5*1, will functionally behave as though they have increased activity and may require higher doses of CYP3A5 metabolized drugs.

 

The following table displays the CYP3A5 variants detected by this assay, the corresponding star allele, and the effect on CYP3A5 enzyme activity:

CYP3A5 allele

cDNA nucleotide change

(NM_000777.4)

Effect on enzyme activity

*1

None (wild type)

Normal activity

*3

c.219-237A>G

No activity

*5

c.432+2T>C

No activity

*6

c.624G>A

No activity

*7

c.1035dup

No activity

*8

c.82C>T

Reduced activity

*9

c.1009G>A

Reduced 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 Pharmacogene Variation (PharmVar) Consortium.(1)

 

For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic 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 (phenotype), additional testing could be considered.

 

Samples may contain donor DNA if obtained from patients who received non-leukoreduced blood transfusions or allogeneic hematopoietic stem cell 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 hematopoietic stem cell transplantation, a pretransplant DNA specimen is recommended for testing.

 

CYP3A5 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient's CYP3A5 status.

 

This method may not detect all variants that result in altered CYP3A5 activity. Therefore, absence of a detectable variant does not rule out the possibility that a patient has altered CYP3A5 activity due to other CYP3A5 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 CYP3A5 catalytic activity.

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

1. PharmVar: Pharmacogene Variation Consortium. Updated March 3, 2021. Accessed March 22, 2021. Available at www.pharmvar.org/

2. Birdwell KA, Decker B, Barbarino JM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015;98(1):19-24. doi: 10.1002/cpt.113

3. Thervet E, Loriot MA, Barbier S, et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin Pharmacol Ther. 2010;87(6):721-726. doi: 10.1038/clpt.2010.17

4. Lamba J, Hebert JM, Schuetz EG, Klein TE, Altman RB. PharmGKB summary: very important pharmacogene information for CYP3A5. Pharmacogenet Genomics. 2012;22(7):555-558. doi: 10.1097/FPC.0b013e328351d47f

5. Clinical Pharmacogenetics Implementation Consortium (CPIC). Accessed October 14, 2020. https://cpicpgx.org/

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