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Test ID: U1A1O UDP-Glucuronosyl Transferase 1A1 TA Repeat Genotype, UGT1A1, Saliva

Reporting Name

UGT1A1 TA Repeat Genotype, Saliva

Useful For

Identifying individuals who are at increased risk of adverse drug reactions with drugs that are metabolized by UGT1A1; especially irinotecan, but also including nilotinib, pazopanib, and belinostat

 

Identifying individuals with Gilbert syndrome due to the presence of homozygous TA7, homozygous TA8, or compound heterozygous TA7/TA8

 

Identifying individuals who are carriers of Gilbert syndrome due to the presence of heterozygous TA7 or TA8

 

Genotyping patients who prefer not to have venipuncture done

Testing Algorithm

See UGT1A1 Test-Ordering Algorithm in Special Instructions.

Specimen Type

Saliva


Advisory Information


This test does not detect or report variants other than the *28 (TA7), *36 (TA5), and *37 (TA8) alleles. Numerous variants outside of the TA repeat region have been described that impair UGT1A1 activity. Sequencing of the full gene is also available for detection of variants outside of the TA repeat region. Order UGT1 / UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Irinotecan Hypersensitivity when evaluating risk for irinotecan toxicity. Order UGT2 / UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Hyperbilirubinemia, if evaluation for Gilbert syndrome or Crigler-Najjar syndrome type I or type II is desired.



Specimen Required


Multiple saliva genotype tests can be performed on a single specimen after a single extraction. See Multiple Saliva Genotype Tests in Special Instructions for a list of tests that can be ordered together.

 

Supplies: DNA Saliva Collection Kit (T651)

Container/Tube: Oragene DNA Self-Collection Kit (T651: fees apply)

Specimen Volume: Full tube

Collection Instructions:

1. Fill tube to line.

2. Send specimen in original container per kit instructions.


Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type Temperature Time
Saliva Ambient

Reference Values

An interpretive report will be provided.

Day(s) and Time(s) Performed

Monday, Wednesday, Friday; Varies

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

81350-UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide AI) (eg, irinotecan metabolism), gene analysis, common variants (eg, *28, *36, *37)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
U1A1O UGT1A1 TA Repeat Genotype, Saliva In Process

 

Result ID Test Result Name Result LOINC Value
32979 TA/TA In Process
32980 Reviewed by No LOINC Needed
32981 UGT1A1 TA Repeat Genotype In Process

Clinical Information

Following primary metabolism by the phase I enzymes (by oxidation, reduction, dealkylation, and cleavage in the intestines and liver), many drugs and their metabolites are further modified for excretion by a group of conjugative, phase II enzymes. One of these phase II enzymes, uridine diphosphate-glycuronosyl transferase 1A1 (UGT1A1), is responsible for phase II conjugation of certain drugs, like irinotecan. UGT1A1 is additionally responsible for glucuronide conjugation of bilirubin, which renders the bilirubin water soluble and permits excretion of the bilirubin-glucuronide conjugates in urine. Reduced UGT1A gene transcription due to variation in the number of thymine-adenine (TA) repeats in the TATA box of the gene promoter results in reduced enzymatic activity and an increased risk for adverse outcomes in response to drugs metabolized by UGT1A1. Such TA repeat variants are also associated with Gilbert syndrome (unconjugated hyperbilirubinemia).

 

The TA repeat number may vary from 5 to 8 TA repeats, with 6 TA repeats being the most common allele (considered the normal allele), resulting in normal UGT1A1 expression. In addition, the rare 5 TA repeat (TA5 or *36: c.-41_-40delTA) has normal UGT1A1 expression. Individuals with 7 TA repeats (TA7 or *28: c.-41_-40dupTA) or the rare 8 TA repeats (TA8 or *37: c.-43_-40dupTATA) have decreased expression of UGT1A1. Approximately 10% to 15% of Caucasians and African Americans are homozygous for the TA7 repeat (*28/*28).

 

UGT1A1 is involved in the metabolism of irinotecan, a chemotherapy drug used to treat solid tumors including colon, rectal, and lung cancers. If UGT1A1 activity is reduced or deficient, the active irinotecan metabolite (SN-38) is less efficiently conjugated with glucuronic acid, which leads to an increased concentration of SN-38. This in turn can result in severe neutropenia; and the combination of neutropenia with diarrhea can be life-threatening. Individuals who are homozygous for *28 (TA7) have a 50% higher risk of experiencing severe (grade 4 or 5) neutropenia following the administration of irinotecan. Approximately 40% of individuals treated with irinotecan are heterozygous for the TA7 repeat allele (ie, TA6/TA7 or heterozygous *28). These individuals are also at increased risk of grade 4 neutropenia. The drug label for irinotecan indicates that individuals homozygous or heterozygous for TA repeat variants have a higher risk for severe or life-threatening neutropenia. The risk is thought to be greatest in individuals who receive irinotecan once every 3 weeks.

 

Additional drugs have also been associated with an increased risk for adverse outcomes if the patient has reduced UGT1A1 enzyme activity. The FDA drug labels for nilotinib, pazopanib, and belinostat all contain warnings for an increased risk (incidence) of adverse outcomes in patients who have reduced activity alleles. Recently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir treatment that indicate patients who are homozygous for a reduced activity (decreased expression) allele should be considered for an alternate medication due to the significant risk for developing hyperbilirubinemia (jaundice).

 

Gilbert syndrome (GS), found in 5% to 10% of the population, is the most common hereditary cause of increased bilirubin and is associated with usually benign, mild hyperbilirubinemia (bilirubin levels are typically around 3 mg/dL). Gilbert syndrome is caused by a 25% to 50% reduced glucuronidation activity of the UGT1A1 enzyme and characterized by episodes of mild intermittent jaundice and the absence of liver disease. Homozygosity for the reduced activity alleles, TA7 and TA8, or compound heterozygosity (TA7/TA8) is consistent with a diagnosis of Gilbert syndrome. Heterozygosity for TA7 or TA8 is consistent with carrier status for Gilbert syndrome.

Interpretation

An interpretive report will be provided.

 

Drug-drug interactions must be considered when predicting the UGT1A1 phenotype, especially in individuals heterozygous for the TA7 polymorphism (see Cautions). 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.

Clinical Reference

1. Innocenti F, Grimsley C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002;12:725-733

2. Gammal R, Court M, Haidar C, et al: Clinical Pharmacogenomics Implementation Consortium (CPIC) Guidelines for UGT1A1 and Atazanavir Prescribing. Clin Pharm Ther. 2015

3. Shibata T, Minami Y, Mitsuma A, et al: Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia. Int J Clin Oncol 2014;19:391-396

4. U.S. Food and Drug Administration, Pharmacogenomic Biomarkers in Drug Labeling. Available at www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm

5. UDP-Glucuronosyltransferase Alleles Nomenclature page. Available at www.pharmacogenomics.pha.ulaval.ca/cms/ugt_alleles

Analytic Time

2 days (Not reported Saturday or Sunday)

Method Name

Polymerase Chain Reaction (PCR) with Fragment Analysis by Capillary Gel Electrophoresis

Forms

New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

Mayo Medical Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

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