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Test ID: U1A1Q UDP-Glucuronosyl Transferase 1A1 TA Repeat Genotype, UGT1A1, Varies


Ordering Guidance


This test does not detect or report variants other than the *1 (TA6), *28 (TA7), *36 (TA5), and *6 (c.211G>A) alleles. The *37 (TA8) allele cannot be distinguished from *28 (TA7) and will be reported as *28 (TA7) by this methodology. 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 UGTFG / UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing.



Specimen Required


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

 

Submit only 1 of the following specimens:

 

Specimen Type: Whole blood

Container/Tube: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Specimen Stability Information: Ambient (preferred) 9 days/Refrigerated 30 days

 

Specimen Type: Saliva

Patient Preparation: Patient should not eat, drink, smoke, or chew gum 30 minutes prior to collection.

Supplies: Saliva Swab Collection Kit (T786)

Specimen Volume: 1 swab

Collection Instructions: Collect and send specimen per kit instructions.

Specimen Stability Information: Ambient 30 days

 

Specimen Type: Extracted DNA

Container/Tube: 2 mL screw top tube

Specimen Volume: 100 mcL (microliters)

Collection Instructions:

1. The preferred volume is 100 mcL at a concentration of 50 ng/mcL.

2. Include concentration and volume on tube.

Specimen Stability Information: Frozen (preferred)/Ambient/Refrigerated


Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. If not ordering electronically, complete, print, and send 1 of the following forms with the specimen:

-Therapeutics Test Request (T831)

Useful For

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

 

Identifying individuals with Gilbert syndrome due to the presence of homozygous UGT1A1*6 (c.211G>A, based on NM_000463.2) allele, TA7, homozygous TA8, or compound heterozygous *6, TA7 or TA8

 

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

Testing Algorithm

See UGT1A1 Test-Ordering Algorithm in Special Instructions.

Method Name

Real-Time Polymerase Chain Reaction (PCR) with Allelic Discrimination Analysis

Reporting Name

UGT1A1 TA Repeat Genotype, V

Specimen Type

Varies

Specimen Minimum Volume

Blood: 0.4 mL
Saliva: 1 swab

Specimen Stability Information

Specimen Type Temperature Time Special Container
Varies Varies

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 (UDP)-glycuronosyl transferase 1A1 (UGT1A1), is responsible for phase II conjugation of certain drugs, like atazanavir, irinotecan, nilotinib, pazopanib, and belinostat. 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 and c.211G>A (*6) results in reduced enzymatic activity and an increased risk for adverse outcomes in response to drugs metabolized by UGT1A1. These variants are also associated with Gilbert syndrome (unconjugated hyperbilirubinemia).

 

The TA repeat number may vary from 5 to 8 TA (TA5-TA8) repeats, with 6 TA (TA6) repeats being the most common allele. TA6 is the reference allele and is considered to have normal UGT1A1 expression. In addition, the rare TA5 repeat (*36: c.-41_-40delTA) has normal UGT1A1 expression. Individuals with TA7 repeat (*28: c.-41_-40dupTA) or the rare TA8 repeat (TA8 or *37: c.-43_-40dupTATA, not distinguished from TA7 with this assay) have decreased expression of UGT1A1. Approximately 10% to 15% of white and African American populations 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 atazanavir, 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).(2)

 

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, UGT1A1*6 (c.211G>A) allele, TA7, and TA8, or compound heterozygosity (*6, TA7, or TA8) is consistent with a diagnosis of Gilbert syndrome. Heterozygosity for *6, TA7 or TA8 is consistent with carrier status for Gilbert syndrome.

Reference Values

An interpretive report will be provided.

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. For additional information regarding pharmacogenomic genes and their associated drugs, see 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 [published correction appears in Pharmacogenetics. 2003 Mar;13(3):183]. Pharmacogenetics. 2002;12(9):725-733. doi: 10.1097/00008571-200212000-00006

2. Gammal RS, Court MH, Haidar CE, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing. Clin Pharmacol Ther. 2016;99(4):363-369. doi: 10.1002/cpt.269

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(2):391-396. doi:1 0.1007/s10147-013-0562-5

4. U.S. Food and Drug Administration: Pharmacogenomic Biomarkers in Drug Labeling. FDA;. Accessed October 14, 2020. Available at www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm

5. UGT Nomenclature Committee: UGT1A and UGT2B haplotypes and SNPs tables. Canada Research Chair in Pharmacogenomics. June 2005. Accessed October 14, 2020. www.pharmacogenomics.pha.ulaval.ca/ugt-alleles-nomenclature/

Day(s) Performed

Monday through Friday

Report Available

3 to 6 days

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 US 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
U1A1Q UGT1A1 TA Repeat Genotype, V 34509-0

 

Result ID Test Result Name Result LOINC Value
610168 UGT1A1 Genotype 93845-6
610169 UGT1A1 Phenotype 79718-3
610170 Interpretation 69047-9
610171 Additional Information 48767-8
610172 Method 85069-3
610173 Disclaimer 62364-5
610174 Reviewed by 18771-6
Mayo Clinic Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

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