Label Name: UGT1A1 GENO
Lab Discipline: Molecular Diagnostics
Institution:  Duke University Health System 
EAP ID:  LAB6885 
Last Review:  3/17/2017 10:07:26 AM
Container & Volume
  Age Group   Container   Volume  
  0  - 18 Years LAVENDER TOP TUBE 3  ML
Collection Notes
  • Peripheral Blood: One lavender-top EDTA tube (minimum of 3 mls) is required for testing. Forward unprocessed peripheral blood promptly to the laboratory at ambient temperatures. THE SPECIMEN CANNOT BE FROZEN. GREEN-TOP (HEPARIN) TUBES ARE NOT ACCEPTABLE FOR TESTING.

    Buccal swab (using the MDL specimen collection kit): Scrape the inside of the mouth using 10 strokes with a sterile nylon bristle cytology brush. Dip the brush up and down 10 times in the provided solution (Cell Lysis Solution) contained in the 1.5mL microfuge tube. Detailed instructions and collection kits are available on request from the Clinical Molecular Diagnostics Laboratory.
  Deliver peripheral blood and buccal swab specimens to laboratory at ambient temperature. If there is a delay of more than 24 hours in delivery, refrigerate the sample. DO NOT FREEZE.
Turn Around Time -  Routine: 7 days   Stat: STAT is Unavailable
Reference Values
Genotypes 6/6, 6/7, 7/7
  This assay uses PCR followed by amplicon nucleotide length analysis to identify DNA sequence variants in the TATA box of the UGT1A1 gene promoter. Genomic DNA is extracted from the patient sample and a single PCR reaction is performed using fluorescently tagged sequence specific oligonucleotide primers that flank the TATA box within the UGT1A1 promoter. Amplification products are resolved by capillary electrophoresis using an ABI 3130xl Fragment Analyzer, and their nucleotide length is determined using GeneMapper software (ABI). This approach detects the common variants in the UGT1A1 TATA box that differ in the number of TA repeats: TA5 (UGT1A1*36); TA6 (UGT1A1*1); TA7 (UGT1A1*28); and TA8 (UGT1A1*37). Other UGT1A1 variants are not detected by this assay.

This test was developed and its performance characteristics determined by the DUHS Clinical Molecular Diagnostics Laboratory. It has not been cleared or approved by the U.S. Food and Drug Administration. This test is used for clinical purposes. It should not be regarded as investigational or for research. This laboratory is certified under the Clinical Laboratory Improvement Amendments of 1988 ("CLIA") as qualified to perform high complexity clinical testing.
Clinical Significance and Interpretive Data

Bilirubin, a product of heme catabolism, is removed from the circulation in peripheral blood and processed by hepatocytes. Glucuronosyltransferase activity in the liver is essential for the conjugation of bilirubin, facilitating its solubilization and successful excretion into bile canaliculi. Hepatic UDP-glucuronosyltransferase (UGT1A1) is the major enzyme isoform which catalyzes the glucuronidation of bilirubin.

Consistent with its essential role in the elimination of bilirubin, mutations in UGT1A1 result in clinical syndromes characterized by unconjugated hyperbilirubinemia. Patients with coding region mutations that profoundly impair UGT1A1 activity develop Crigler-Najjar Syndrome. These individuals may present with severe jaundice and encephalopathy if untreated. Alternatively, patients with a modest reduction in UGT1A1 activity have Gilbert Syndrome. These patients present with mild hyperbilirubinemia which often remains asymptomatic until physiologic stresses raise serum bilirubin concentrations.

Gilbert syndrome is commonly, though not exclusively, associated with polymorphisms in the promoter region of the UGT1A1 gene. Variable copy numbers of TA repeats in the transcription initiation site of the UGT1A1 gene are responsible for polymorphic mRNA and protein expression levels. Common allelic variants include UGT1A1*1 with six TA repeats (TA6) and UT1A1*28 with seven TA repeats (TA7). Other alleles with five and eight TA repeats exist; however, they account for < 10% of TA promoter polymorphisms in North American individuals of European, Asian and African ancestry (3) . Thus, in an individual with two UGT1A1 alleles, three possible genotypes are commonly seen (TA6/TA6, TA6/TA7, TA7/TA7). The number of TA repeats affects expression of the UGT1A1 gene, with UGT1A1*28 (TA7) having reduced expression levels when compared to UGT1A1*1 (TA6) (1). Gilbert Syndrome is often associated with homozygosity for the UGT1A1*28 allele (TA7/TA7) in Caucasians. However, not all individuals with two copies of the UGT1A1*28 allele have increased levels of serum bilirubin (1). UGT1A1*28 homozygosity (TA7/TA7) is common, with 10-15% of the Caucasian population in North America homozygous for the TA7 allele.


Studies in cancer patients treated with the topoisomerase inhibitor Irinotecan (CAMPTOSAR) have demonstrated an increase in severe toxicity (grade 4 leukopenia, grade 3-4 neutropenia and/or grade 3-4 diarrhea) in patients with at least one UGT1A1*28 (TA7) allele. In studies of Caucasian patients treated with Irinotecan for predominantly colorectal cancers, the rates of these severe toxicities are 0-17% in UGT1A1*1 homozygotes (TA6/TA6), 12-40% in UGT1A1*1/UGT1A1*28 heterozygotes (TA6/TA7), and 20-71% in UGT1A1*28 homozygotes (TA7/TA7) (4-7). Clearance of Irinotecan's active metabolite SN-38 predominantly occurs through glucuronidation by UGT1A1. Therefore the observed increase in toxicity associated with the low-expression UGT1A1*28 (TA7) allele is thought to be due to decreased clearance of Irinotecan (8). A reduction in initial clinical dosing of Irinotecan should be considered in patients homozygous for TA7 (9); however, the dose which decreases the risk of toxicity while maintaining therapeutic effect is not known. In addition, some patients homozygous for UGT1A1*28 tolerate normal doses of Irinotecan. Less clinical information is available about the relationship of other UGT1A1 alleles and Irinotecan; however, at least some polymorphisms not detected in this assay may contribute to altered sensitivity to Irinotecan toxicity (4). The Food and Drug Administration (FDA) notes that this assay is intended for use as an aid in making individualized patient decisions rather than as a substitute for expert clinical judgment. Other important factors such as liver and kidney function, age, and co-administered drugs should be considered.

Individuals with Gilbert Syndrome have reduced UDP-glucuronosyltransferase activity which is most commonly caused by homozygosity for the UGT1A1*28 allele. However, other genetic mutations can cause Gilbert Syndrome including a missense mutation in the coding region of the UGT1A1 gene (G71R, also called UGT1A1*6) common in the Asian population (10). The UGT1A1 Molecular Assay only identifies two common polymorphisms in the TATA box promoter region of this gene, UGT1A1*1 (TA6) and UGT1A1*28 (TA7). Therefore, this test cannot be used to evaluate all clinically relevant UGT1A1 variants. In addition, given the high prevelance of the TA7 allele, homozygosity for TA7 does not exclude the possibility of more serious causes of an increased blood level of unconjugated bilirubin and jaundice. Thus, these results should be interpreted in conjunction with clinical history, family history and other physical and laboratory findings.


1. PJ Bosma et al (1995). The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med, 333(18): 1171-5.

2. G Monaghan et al (1996). Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome. Lancet, 347(9001): 578-81.

3. E Beutler et al (1998). Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A, 95(14): 8170-4.

4. Y Ando et al (2000). Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res, 60(24): 6921-6.

5. F Innocenti et al (2004). Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol, 22(8): 1382-8.

6. E Rouits et al (2004). Relevance of different UGT1A1 polymorphisms in irinotecan-induced toxicity: a molecular and clinical study of 75 patients. Clin Cancer Res, 10(15): 5151-9.

7. E Marcuello et al (2004). UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer, 91(4): 678-82.

8. S Nagar et al (2006). Pharmacogenetics of uridine diphosphoglucuronosyltransferase (UGT) 1A family members and its role in patient response to irinotecan. Drug Metab Rev, 38(3): 393-409.

9. RP Ramchandani et al (2007). The role of SN-38 exposure, UGT1A1*28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity. J Clin Pharmacol, 47(1): 78-86.

10. K Akaba et al (1999). Neonatal hyperbilirubinemia and a common mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese. J Hum Genet, 44(1): 22-5.
    This test can be used to:

• Identify a genetic risk factor for having toxic drug side effects (a TA7 allele in the UGT1A1 gene) in individuals undergoing treatment with the anticancer drug Camptosar® (irinotecan HCl).

• To Provide genetic confirmation of a Gilbert's Syndrome diagnosis.
    •This assay detects the common variants in the UGT1A1 TATA box that differ in the number of TA repeats: TA5 (UGT1A1*36); TA6 (UGT1A1*1); TA7 (UGT1A1*28); and TA8 (UGT1A1*37). Other UGT1A1 variants are not detected by this assay.

• This test is subject to interference by various factors such as DNA quality, presence of mutation and polymorphism of UGT1A1 gene sequence, etc.

• An inaccurate genotype information may result if this test is performed on peripheral blood genomic DNA of patients who have undergone a bone marrow or liver transplant or received a ganulocyte transfusion. In this situation testing on a buccal specimen may be considered.
Test Synonyms
  Synonym(s): Camptostar
Synonym(s): Gilbert's Syndrome
Synonym(s): Gilberts
Synonym(s): Irinotecan
Molecular Diagnostics Laboratory

Medical Director:
 Michael Datto, M.D., Ph.D.
 Phone: 919-684-6965
 Email: michael.datto@duke.edu
Lab Director:
 Catherine Rehder Ph.D, FACMG
 Phone: 919-613-8434
 Email: catherine.rehder@duke.edu
Lab Director:
 Siby Sebastian Ph.D., DABMG
 Phone: 919-613-8432
 Email: siby.s@duke.edu

 Wadsworth Bldg, Cytogenetics, Rm 0220
 2351 Erwin Rd
 Durham,  NC  27705
 Phone: 919-684-2698
 FAX: 919-668-5424

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