Overview
UGT1A1*28 variant homozygosity refers to a genetic condition where both copies of the UGT1A1 gene carry the *28 variant. This variant is characterized by the presence of seven TA repeats in the promoter region instead of the usual six. The additional repeat reduces transcription efficiency, which leads to lower expression of the UGT1A1 enzyme. As a result, the body’s ability to metabolize certain substances, especially specific drugs and bilirubin, is reduced. This variant is relatively common in individuals of African and European ancestry and less frequent in East Asian populations. Its clinical importance is mainly linked to drug metabolism and toxicity, particularly in patients receiving irinotecan chemotherapy.
What the UGT1A1 Gene Does
The UGT1A1 gene encodes the enzyme UDP-glucuronosyltransferase 1A1, which plays a key role in glucuronidation. This process helps the body break down and eliminate various endogenous and exogenous compounds. UGT1A1 is primarily expressed in the liver but is also present in the colon, intestine, and stomach. One of its important functions is the metabolism of irinotecan, a commonly used chemotherapeutic drug. Reduced activity of this enzyme can cause accumulation of active drug metabolites, increasing the risk of toxicity. UGT1A1 also contributes to bilirubin clearance, and reduced enzyme activity is associated with elevated bilirubin levels.
Clinical Relevance
UGT1A1*28 homozygosity has significant clinical relevance in oncology and inherited metabolic conditions. Patients with this genotype are at a higher risk of developing severe adverse effects when treated with UGT1A1-metabolized drugs. In the context of irinotecan therapy, this can include serious complications such as grade 4 neutropenia and severe diarrhea. Beyond chemotherapy, reduced UGT1A1 activity is also linked to conditions involving impaired bilirubin metabolism, such as Gilbert syndrome. Identifying this genotype before initiating treatment allows clinicians to adjust drug dosing and reduce the likelihood of harmful side effects.
Indications for Testing
Testing for UGT1A1*28 homozygosity is recommended in several clinical situations. It is useful in patients who show clinical signs or symptoms suggestive of Gilbert syndrome or those with a relevant family history. Genetic testing is also advised before starting irinotecan hydrochloride therapy to assess the risk of toxicity. The test is commonly indicated in patients with colorectal, lung, gastric, and gynecologic cancers, where irinotecan or other UGT1A1-metabolized drugs may be part of the treatment plan. Early identification of the genotype helps guide safer and more effective treatment decisions.
Methods of Detection
UGT1A1*28 homozygosity is typically detected using next-generation sequencing. This method allows accurate identification of gene sequence variants and provides reliable information about the patient’s genotype. Molecular testing offers high sensitivity and specificity, making it suitable for routine clinical use, especially in oncology and pharmacogenomics settings.
Sample Collection
Several types of samples can be used for UGT1A1 testing. Whole blood is commonly collected, usually 6 ml in an EDTA or citrate tube, and maintained at ambient temperature. Bone marrow samples may also be used, with around 3 ml collected in similar tubes. In some cases, cells collected from the mouth or saliva can serve as an alternative, non-invasive source of genetic material. Proper sample handling is essential to ensure accurate test results.
Deficiency and Associated Conditions
UGT1A1 deficiency affects the clearance of heme metabolites in the liver. Severe deficiency is seen in Crigler–Najjar disease, a rare inherited disorder characterized by chronic and severe jaundice due to very high bilirubin levels. Although UGT1A1*28 homozygosity is typically milder, it can still lead to hyperbilirubinemia. Dietary approaches that may help support UGT1A1 activity include foods from families such as cruciferous vegetables, citrus fruits, onions, and legumes, which are known to influence enzyme expression.
Prognostic and Pharmacogenomic Significance
From a pharmacogenomic perspective, UGT1A1 testing has strong prognostic value. The test screens for gene variants associated with an increased risk of adverse drug reactions. Drugs affected by UGT1A1 activity include irinotecan, atazanavir, belinostat, nilotinib, pazopanib, and sacituzumab govitecan. Knowing a patient’s UGT1A1 status helps clinicians tailor drug doses, reduce toxicity, and improve overall treatment outcomes. By integrating genetic information into clinical decision-making, side effects such as neutropenia and severe diarrhea can be minimized while maintaining therapeutic effectiveness.
