UGT1A1 Gene Polymorphism (TA Repeat)

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Detects Gilbert’s syndrome polymorphism.

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UGT1A1 Gene Polymorphism (TA Repeat) - Comprehensive Medical Test Guide

Why is it done?
- Test Purpose: Identifies genetic variations in the UGT1A1 gene that affect the enzyme UDP-glucuronosyltransferase 1A1, which is responsible for metabolizing bilirubin and certain medications
- Primary Indications: Diagnosis of Gilbert's syndrome, assessment of irinotecan (Camptosar) toxicity risk, evaluation of elevated unconjugated hyperbilirubinemia, and personalized medicine for chemotherapy dosing
- Pharmacogenomic Applications: Predicting adverse drug reactions to medications metabolized by UGT1A1, including atazanavir, nilotinib, and other therapeutic agents
- Clinical Scenarios: Before initiating irinotecan chemotherapy, when patients present with unexplained jaundice, family history of Gilbert's syndrome, or prior adverse drug reactions
Normal Range
- TA Repeat Genotypes: The UGT1A1 promoter region contains a TATA box with variable TA repeats
- Normal Genotype (TA)7/(TA)7: Two copies of seven TA repeats; represents normal UGT1A1 enzyme activity; normal bilirubin conjugation; minimal adverse drug reaction risk
- Heterozygous (TA)6/(TA)7 or (TA)7/(TA)8: Intermediate enzyme activity; mild to moderate reduction in bilirubin conjugation; moderately increased risk for adverse effects with certain medications
- Homozygous Variant (TA)6/(TA)6 or (TA)8/(TA)8: Reduced enzyme activity; significantly decreased bilirubin conjugation capacity; substantially elevated adverse drug reaction risk
- Interpretation Key: Results are qualitative (genetic variants present/absent), not quantitative; enzyme activity correlates with TA repeat number
Interpretation
- (TA)7/(TA)7 Genotype - Normal Metabolizer: Normal UGT1A1 enzyme expression and activity; approximately 30-40% of Caucasian population; bilirubin levels typically 0.1-1.2 mg/dL; standard medication dosing appropriate; low risk for Gilbert's syndrome or irinotecan toxicity
- (TA)6/(TA)7 or (TA)7/(TA)8 Genotype - Intermediate Metabolizer: Reduced UGT1A1 enzyme activity (approximately 30% reduction); mildly elevated unconjugated bilirubin (1-3 mg/dL); increased irinotecan toxicity risk (FDA recommends dose reduction); possible mild hyperbilirubinemia under stress conditions; monitor closely for adverse drug reactions
- (TA)6/(TA)6 Genotype - Poor Metabolizer: Severely reduced UGT1A1 enzyme activity (approximately 70% reduction); significantly elevated unconjugated bilirubin (typically 2-6 mg/dL); consistent with Gilbert's syndrome diagnosis; high irinotecan toxicity risk (FDA recommends 25-30% dose reduction or possible contraindication); significantly increased risk for adverse drug reactions; may cause visible jaundice
- (TA)8/(TA)8 Genotype - Rare Variant: Increased UGT1A1 enzyme activity; lower bilirubin levels; enhanced drug metabolism; rare in most populations; may require higher medication doses for therapeutic efficacy
- Factors Affecting Interpretation: Stress, illness, fasting, and dehydration can increase bilirubin levels; ethnicity influences genotype frequency (African ancestry: higher (TA)6; Asian ancestry: higher (TA)7); concurrent liver disease or hemolysis can elevate bilirubin independently; other UGT1A1 variants may also be present
Associated Organs
- Primary Organ System - Liver: UGT1A1 is expressed primarily in hepatocytes; dysfunction affects bilirubin conjugation capacity; impairs Phase II drug metabolism in the liver
- Gilbert's Syndrome: Benign hereditary condition characterized by mild unconjugated hyperbilirubinemia; caused by reduced UGT1A1 activity; affects 3-10% of population; (TA)6/(TA)6 genotype associated with classic presentation; characterized by fluctuating jaundice, fatigue, and abdominal discomfort; generally benign but requires medication adjustment
- Irinotecan Toxicity Risk: Severe neutropenia, diarrhea, and toxicity in patients with (TA)6/(TA)6 or (TA)6/(TA)7 genotypes; UGT1A1 metabolizes active metabolite SN-38; impaired metabolism leads to drug accumulation; FDA Black Box warning for irinotecan in UGT1A1 poor metabolizers
- Associated Medical Conditions: Neonatal jaundice in newborns with UGT1A1 variants; Crigler-Najjar syndrome (complete UGT1A1 deficiency, different from TA repeat polymorphism); hemolytic anemia complications; drug-induced liver injury risk with certain medications
- Secondary Organs Affected: Bone marrow (hematologic toxicity from impaired drug metabolism); gastrointestinal tract (severe diarrhea and mucositis); kidneys (indirect effects from severe systemic toxicity); skin (possible jaundiced appearance)
- Complications Associated with Abnormal Results: Life-threatening chemotherapy-induced neutropenia, uncontrolled diarrhea leading to dehydration, bilirubin encephalopathy in neonates, recurrent hospitalizations, reduced quality of life from medication adverse effects, potential treatment delays in cancer therapy
Follow-up Tests
- Bilirubin Level Testing: Total and direct (conjugated) bilirubin measurement; unconjugated bilirubin calculation; helps confirm Gilbert's syndrome diagnosis and correlate with genotype; baseline and periodic monitoring recommended
- Liver Function Tests: ALT (alanine aminotransferase), AST (aspartate aminotransferase), alkaline phosphatase, GGT (gamma-glutamyl transferase); rules out concurrent hepatic disease; distinguishes Gilbert's syndrome from other causes of hyperbilirubinemia
- Complete Blood Count (CBC): Evaluates for hemolytic anemia or reticulocytosis; helps exclude hemolysis as cause of elevated bilirubin; baseline before chemotherapy initiation
- Additional UGT1A1 Variants: Testing for other UGT1A1 mutations (e.g., G71R, P229Q, Y486D); comprehensive pharmacogenomic panels; identifies patients with severely reduced function beyond TA repeat variants alone
- Pharmacogenomic Panels: Expanded testing including CYP3A4, CYP2C variants; comprehensive drug metabolism assessment; personalized medicine optimization for multiple medications
- Abdominal Imaging: Ultrasound or CT imaging if jaundice is severe or concerning; rules out biliary obstruction or hepatic pathology; indicated if unconjugated hyperbilirubinemia is marked or accompanied by other liver test abnormalities
- Ongoing Monitoring: If receiving irinotecan: CBC monitoring before each cycle, during treatment, and after completion; assess for neutropenia and severe toxicity; bilirubin monitoring during chemotherapy; consider dose adjustments for (TA)6/(TA)6 genotype
- Periodic Reevaluation: Annual or biennial bilirubin testing for Gilbert's syndrome patients; medication reviews when new drugs are initiated; reassessment if new symptoms of jaundice or malaise develop
Fasting Required?
- Fasting Requirement: NO - UGT1A1 gene polymorphism testing is a genetic test that does not require fasting; food intake does not affect genotype results; test can be performed at any time of day
- Sample Collection: Blood sample via venipuncture (EDTA or other specified tube); alternatively, saliva sample may be used depending on laboratory; DNA extraction from blood cells or buccal cells used for genotyping
- Timing Considerations: Genetic test results are permanent and unaffected by time of day; can be drawn morning, afternoon, or evening; however, if concurrent bilirubin testing is ordered, fasting may be recommended for 9-12 hours as bilirubin can be affected by hydration and stress
- Medications: No medications need to be held prior to genetic testing; all routine medications can be taken as prescribed; herbal supplements do not interfere with results
- Patient Preparation Instructions: Avoid prolonged stress or strenuous exercise immediately before testing if bilirubin is also being measured; bring photo identification and insurance card; inform phlebotomist of any bleeding disorders or anticoagulant use (though rare genetic tests are affected); no special clothing required
- Specimen Stability: Blood samples in EDTA tubes stable for several days at room temperature; samples can be refrigerated or frozen for longer-term storage; DNA does not degrade rapidly; no special transport conditions required for most laboratories

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