UDP-Glucuronosyl Transferase 1A1 (UGT1A1) Gene, Known Mutation
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Excess levels of bilirubin, which is a by-product of heme, have been associated with deleterious health effects. Uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1) is responsible for bilirubin conjugation with glucuronic acid. This renders the bilirubin water soluble and permits excretion of the bilirubin-glucuronide conjugates in urine.(1) Genetic variants in the UGT1A1 gene may cause reduced or absent UGT1A1 enzymatic activity resulting in hyperbilirubinemia.
Gilbert syndrome, found in 5% to 10% of the population, is the most common hereditary cause of increased bilirubin and is associated with mild hyperbilirubinemia (bilirubin levels are typically around 3 mg/dL).(2) 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.
Crigler-Najjar (CN) syndrome types I and II are inherited causes of severe unconjugated hyperbilirubinemia. CN type I is associated with the complete absence of UGT1A1 activity and usually presents as intense jaundice in the first days of life and persists thereafter.(3) CN type II is a milder form of hyperbilirubinemia, as compared to CN type I, with at least partial UGT1A1 activity. Phenobarbital, a drug that induces synthesis of a number of hepatic enzymes, is effective in decreasing serum bilirubin levels by approximately 25% in patients with CN type II; CN type I does not respond to phenobarbital treatment.
If left untreated, the buildup of bilirubin in a newborn can cause kernicterus, which is bilirubin-induced brain damage. In addition to phenobarbital, treatments of CN may include: phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate, and liver transplantation.
The UGT1A1 gene maps to chromosome 2q37 and contains 5 exons. This test is intended for analysis of a specific UGT1A1 gene variant or variants that have already been identified in an affected family member. Analysis is performed for the familial variants only.
Identifying the presence of a UGT1A1 variant when the variant has been previously identified in a family member (carrier or affected)
An interpretive report will be provided.
UGT1A1 is a pharmacogene and patients with reduced UGT1A1 enzyme activity are at risk for adverse outcomes with certain drugs. The FDA drug labels for nilotinib, pazopanib, and belinostat all contain warnings for an increased risk (incidence) of adverse outcomes in patients who have UGT1A1 alleles associated with reduced activity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir treatment, indicating that patients with homozygous UGT1A1 alleles associated with reduced activity or decreased expression should consider an alternate medication due to a significant risk for developing hyperbilirubinemia (jaundice).
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Blood 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.
UGT1A1 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient's UGT1A1 status.
This test is for individuals who may harbor a UGT1A1 variant that has been previously identified in the family. If the familial variant is not known, the familial proband should be screened for UGT1A1 variants using UGT2 / UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Hyperbilirubinemia.
This assay does not rule out the presence of other variants within this gene. This test is used to detect only known (previously identified) familial variants occurring in the promoter, exons, exon-intro boundaries, and the region in the distal promoter called the "phenobarbital response enhancer module."
An alternative splice site for exon 5 (referred to as exon 5b) has been discovered and described in the literature. This new exon is described to have a decrease in enzymatic activity (compared with exon 5a: previously known as exon 5), but little is known about the frequency of exon 5b or how it impacts hyperbilirubinemia. Currently, we are not testing or sequencing exon 5b; we continue to monitor the literature for new information on exon 5b.
Rare variants exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
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.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Guilemette C: Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 2003;3:136-158
2. 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
3. Costa E, Vieira E, Martins M, et al: Analysis of the UDP-glucuronosyltransferase gene in Portuguese patients with a clinical diagnosis of Gilbert and Crigler-Najjar syndromes. Blood Cells Mol Dis 2006;36:91-97
4. Kitagawa C, Ando M, Ando Y, et al: Genetic polymorphism in the Phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics 2005;15:35-41