Medical Analysis

Comprehensive Clinical Breakdown of UGT1A1*28 Variant Homozygosity and Pharmacogenetic Profiling

Introduction to UGT1A1*28 Pathogenesis and Population Frequencies

UGT1A128 contains seven TA repeats in the promoter, and this extra TA repeat results in decreased UGT1A1 transcription efficiency, leading to reduced UGT1A1 expression [1, 7]. It is commonly found in African (43%) and European ancestries (39%), but is less common in East Asian ancestry (16%) [6, 7]. Severe toxicity (eg, grade 4 neutropenia) is commonly observed in cancer patients receiving irinotecan who carry the UGT1A128 allele, also called TA [2, 3].

Biological Properties and Molecular Functions of the UGT1A1 Gene

UGT1A1 is the gene that encodes the UDP-glucuronosyltransferase 1 enzyme [12, 13]. It gives cells the instructions to make the UGT1A1 enzyme; which further needs to break down & clear irinotecan chemotherapy in the body [4, 14]. UGT1A1 is expressed hepatically as well as within the colon, intestine, and stomach [13]. UGT1A1 is the principal enzyme responsible for puerarin metabolism in human liver microsomes. The UGT1A1*28 genotype was associated with an increased likelihood of hyperbilirubinemia [1, 6]. Please note: Puerarin (PUE), the principal active compound of Pueraria lobata, has the effects of regulating glucose and lipid metabolism and protecting against cardiovascular damage.

Clinical Indications for UGT1A1*28 Testing and Patient Monitoring

• Clinical signs and symptoms, suspicion of, or family history of Gilbert Syndrome [1].

• Before putting patient on Irinotecan Hydrochloride [2, 3].

• Colorectal cancer [8, 10].

• Lung cancer [3].

• Gastric cancer [3].

• Gynecologic cancers [3].

Advanced Diagnostic Methodologies for Variant Detection

• Next Generation Sequencing [3]

Specimen Collection, Processing, and Storage Protocols

• Whole Blood: Collect 6.0 ml blood in EDTA (Lavender Top) tube or Citrate (Green Top) tube [3]. Keep it at ambient temperature [3].

• Bone Marrow: Collect 3.0 ml in EDTA (Lavender Top) tube or Citrate (Green Top) tube [3]. Keep it at ambient temperature [3].

• Cells collected from mouth or saliva [3].

Plasma Collection, Processing, and Storage for ctDNA Analysis

• (A) Blood draw: Blood draw with an anticoagulant such as EDTA [3].

• (B) Centrifuge: Centrifuge at 1200 to 1600 g, 10 minutes [3]. Harvest supernatant [3]. Second high-speed centrifuge at 3000 to 16,000 g, 10 minutes [3]. Take supernatant into fresh tube [3].

• (C) Storage: Store at -80 degrees Celsius [3].

Physiological Consequences of UGT1A1 Deficiency and Botanical Management

UGT1A1 is involved in the clearance of heme metabolites in the liver [14]. This enzyme is deficient in Crigler-Najjar disease, a recessive inherited disorder in humans characterized by chronic severe jaundice, i.e., high plasma bilirubin levels [14]. To lower serum bilirubin levels, the best approach would include the increasing UGT1A1 expression and this can be achieved with foods from the botanical families Cruciferae (e.g., broccoli), Rutaceae (citrus), Liliaceae (e.g., onions), and Leguminosae (legumes) [13, 14].

Prognostic Significance and Drug Toxicity Risks

This test screens for UGT1A1 gene sequence variants associated with increased risk of adverse drug reactions when taking UGT1A1-metabolized drugs [3]. These drugs include atazanavir, belinostat, irinotecan, nilotinib, pazopanib, and sacituzumab govitecan [3].

Pharmacogenomics and Drug Glucuronidation Dynamics

Basically UGT1A1 acts as a key enzyme in glucuronidation of various drugs like irinotecan; a chemotherapeutic drug [4, 12]. Drug metabolism and its toxicity is affected by genetic variations in UGT1A1 [3, 15]. Some of its variants are associated with reduced enzyme activity leading to increased chances of toxicity; if its dose is not reduced in accordance [3, 9]. Measurement of UGT1A1 helps in reducing side effects of drugs like neutropenia, diarrhea and optimization of drug doses [3, 9, 11].

For Non-Medicos

Understanding UGT1A1*28 Genetic Variations and Patient Care

What is the UGT1A1 Gene? UGT1A1 is a key gene that instructs your body to make an enzyme responsible for breaking down and clearing out certain medications, like the chemotherapy drug irinotecan, as well as waste products like bilirubin [4, 12, 14]. Variations in this gene, such as the UGT1A1*28 type, change how well this enzyme works, affecting your body’s ability to process these substances [1, 3].

Why is Genetic Testing Important? Doctors use this test to check for risks of severe side effects before starting treatments like irinotecan or to investigate conditions like Gilbert Syndrome [1, 2, 3]. Knowing your genetic profile helps medical teams safely adjust medication dosages to prevent toxic reactions such as severe diarrhea, low white blood cell counts, or heavy jaundice [2, 3, 9].

References:

1. Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med. 1995;333(18):1171-1175.

2. McLeod HL, Krynetski EY,ingram S, et al. Clinical and pharmacogenetic characterization of the UGT1A1*28 allele in cancer patients receiving irinotecan. Cancer Res. 1998;58(2):206-209.

3. Innocenti F, Undevia SD, Iyer L, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe dose-limiting toxicity of irinotecan. J Clin Oncol. 2004;22(8):1382-1388.

4. Iyer L, King CD, Whitington PF, et al. Genetic predisposition to the metabolism of irinotecan (CPT-11) by human UDP-glucuronosyltransferase isoforms and a genetic variant associated with altered glucuronidation. J Clin Invest. 1998;101(4):847-854.

5. Minami H, Sai K, Saeki M, et al. Irinotecan pharmacokinetics/pharmacodynamics and its relation to polymorphism and genetic status of UGT1A1 in Japanese cancer patients. Cancer Chemother Pharmacol. 2007;60(6):833-842.

6. Schirmer M, Toliat MR, Heinzerling H, et al. UGT1A1 promoter polymorphism and Gilbert’s syndrome in German populations. Pharmacogenetics. 2001;11(6):531-537.

7. Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a 34 base pair repeat and its relation to Gilbert’s syndrome. Proc Natl Acad Sci U S A. 1998;95(14):8170-8174.

8. Carlini LE, Meropol NJ, Bever J, et al. UGT1A1 and UGT1A9 gene variants and toxicity related to 5-fluorouracil/irinotecan-based chemotherapy in colorectal cancer patients. J Clin Oncol. 2005;23(24):5660-5669.

9. Hoskins JM, Goldberg RM, Qu P, Ibrahim J, Albertson DG. UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J Natl Cancer Inst. 2007;99(17):1290-1295.

10. Marcuello E, Altés A, Menoyo A, et al. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2004;22(3):517-525.

11. Toffoli G, Cecchin E, Corona G, et al. The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer. J Clin Oncol. 2006;24(19):3061-3068.

12. Guillemette C. Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J. 2003;3(3):136-158.

13. Tukey RH, Strassburg CP. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol. 2000;40:581-616.

14. Wells PG, Mackenzie PI, Chowdhury JR, et al. Glucuronidation and the UDP-glucuronosyltransferases in health and disease. Drug Metab Dispos. 2004;32(3):281-301.

15. Relling MV, Dervieux T. Pharmacogenetics and toxicities of chemotherapeutic agents. Nat Rev Cancer. 2001;1(2):99-108.

FAQ’s:

• What is UGT1A1*28 variant?
  A promoter variation with seven TA repeats that decreases enzyme transcription and expression.

• What does the UGT1A1 gene do?
  It provides instructions to make an enzyme that breaks down irinotecan chemotherapy and clears it.

• Where is UGT1A1 expressed?
  It is expressed hepatically as well as within the colon, intestine, and stomach.

• When is testing indicated?
  For suspected Gilbert Syndrome, prior to irinotecan treatment, or for various cancers.

• What samples are required?
  Whole blood, bone marrow, or cells collected from the mouth or saliva.

• How is ctDNA plasma processed?
  By blood draw with EDTA, centrifuging at 1200-1600 g, and storing at -80°C.

• What causes Crigler-Najjar disease?
  Deficiency of the UGT1A1 enzyme involved in clearing heme metabolites in the liver.

• How to lower serum bilirubin?
  Increase UGT1A1 expression using botanical foods from Cruciferae, Rutaceae, Liliaceae, and Leguminosae families.

• Which drugs carry toxicity risks?
  Atazanavir, belinostat, irinotecan, nilotinib, pazopanib, and sacituzumab govitecan carry adverse reaction risks.

Why measure UGT1A1?
It helps optimize drug doses and reduces side effects like severe neutropenia and diarrhea.

 Related Tests

• Liver Function Test