UGT1A1 rs8175347: Understanding Gilbert's Syndrome and Drug Response
The rs8175347 variant is a genetic change in the promoter region of the UGT1A1 gene that affects how the body processes bilirubin and certain medications. It is widely recognized for its association with Gilbert's syndrome and its role in predicting potential toxicity for patients prescribed the chemotherapy drug irinotecan.
What each genotype means
Normal enzyme activity
This genotype corresponds to the wild-type promoter sequence, often referred to as the *1 allele. Individuals with this profile typically have normal UGT1A1 enzyme activity and are at standard risk for irinotecan-related toxicity. Please discuss any medication dosing with your clinician or pharmacist.
This is the most common genotype in most global populations.
Reduced enzyme activity
This genotype indicates you carry one copy of the variant associated with reduced UGT1A1 enzyme function, often linked to the *28 allele (a TA insertion). This may result in slightly elevated bilirubin levels or a higher sensitivity to certain medications like irinotecan. Please discuss any medication dosing with your clinician or pharmacist.
This genotype is common, found in approximately 30-40% of individuals of European and African ancestry.
Low enzyme activity
This genotype indicates you carry two copies of the variant associated with significantly reduced UGT1A1 enzyme function, commonly known as the *28/*28 genotype. This is frequently associated with Gilbert's syndrome and may increase the risk of severe side effects from specific drugs like irinotecan. Please discuss any medication dosing with your clinician or pharmacist.
This genotype is found in approximately 5-10% of individuals of European and African ancestry, but is much rarer in East Asian populations.
What is the rs8175347 Variant?
The rs8175347 variant is a variation in the number of TA repeats within the promoter region of the UGT1A1 gene. This region, often referred to as the TATA box, acts as a control switch for the gene's activity. While the standard sequence typically contains six TA repeats, the rs8175347 variant involves an expansion to seven or more repeats. This structural change reduces the efficiency of the gene's promoter, leading to lower production of the UGT1A1 enzyme. Because this enzyme is essential for the glucuronidation pathway—a process that makes substances water-soluble for excretion—a reduction in its activity can lead to the accumulation of specific compounds in the body. This variant is frequently studied in pharmacogenomics because it serves as a key marker for identifying individuals who may process certain drugs differently than the general population.
The Role of the UGT1A1 Gene
The UGT1A1 gene provides instructions for making an enzyme called UDP-glucuronosyltransferase 1A1. This enzyme is primarily responsible for the glucuronidation of bilirubin, a yellow pigment produced during the normal breakdown of red blood cells. By attaching a sugar molecule to bilirubin, the enzyme makes it water-soluble, allowing it to be safely excreted from the body through bile and urine. Beyond bilirubin, this enzyme also plays a critical role in metabolizing various drugs, including the chemotherapy agent irinotecan. When UGT1A1 activity is significantly reduced, as seen in conditions like Gilbert's syndrome or Crigler-Najjar syndrome, the body struggles to clear these substances efficiently. This can lead to mild, intermittent jaundice or, in the context of medical treatment, an increased risk of adverse drug reactions due to the slower clearance of active drug metabolites from the bloodstream.
Research and Clinical Associations
Research has firmly established a link between the rs8175347 variant and Gilbert's syndrome, a common, benign condition characterized by mild, unconjugated hyperbilirubinemia. In the field of pharmacogenomics, this variant is highly significant for patients undergoing treatment with irinotecan. Clinical guidelines, such as those from the Clinical Pharmacogenetics Implementation Consortium (CPIC), use this variant to help clinicians adjust irinotecan dosages to minimize the risk of severe toxicity, such as neutropenia and diarrhea. While the association with Gilbert's syndrome is well-documented, the impact on drug metabolism can be complex. Some studies suggest that other genetic factors within the UGT1A gene complex may also influence how a patient responds to medication. Therefore, while rs8175347 is a powerful tool for risk assessment, it is often viewed as one piece of a larger genetic puzzle that clinicians consider when tailoring therapeutic strategies for individual patients.
Population Frequency and Diversity
The frequency of the rs8175347 variant varies significantly across different global populations. The low-activity alleles, such as the seven-repeat sequence, are found worldwide but show distinct patterns of prevalence. Research indicates that these alleles are particularly common in populations of African descent, where they occur at higher frequencies compared to other groups. Conversely, the variant is less common in many Asian populations, where different mutations in the UGT1A1 gene are more frequently associated with reduced enzyme function. Because of this variability, the clinical implications of the variant can differ depending on an individual's ancestral background. Understanding these population-specific frequencies is essential for researchers and clinicians to provide accurate, equitable genetic counseling and to ensure that pharmacogenetic testing is interpreted correctly within the context of a patient's unique genetic heritage.
What You Can Do With This Information
If you have information about your rs8175347 status, it is important to view it as a tool for informed communication with your healthcare provider rather than a standalone medical diagnosis. This variant is primarily relevant in clinical settings, particularly if you are ever prescribed medications like irinotecan or other drugs metabolized by the UGT1A1 enzyme. You cannot use this information to diagnose yourself with Gilbert's syndrome or to make decisions about your medication dosages. If you are concerned about your bilirubin levels or are scheduled to begin a new medication, share your genetic information with your doctor or a pharmacist. They can interpret these results in the context of your overall health, medical history, and current treatment plan. Always consult a qualified medical professional before making any changes to your healthcare regimen or interpreting genetic data in a clinical context.
How common is this variant?
The frequency of the low-activity (TA)7 allele is variable globally, with the highest frequencies observed in populations of African descent and lower frequencies in Asian populations.
Frequently asked questions
Is Gilbert's syndrome a dangerous condition?
Gilbert's syndrome is generally considered a benign, mild condition that does not require treatment. Most people with the condition live healthy lives and may only experience mild jaundice during times of stress, illness, or fasting.
Does having the rs8175347 variant mean I have Gilbert's syndrome?
Not necessarily. While the variant is associated with the condition, having the genotype does not guarantee that you will experience symptoms. A diagnosis of Gilbert's syndrome is typically made by a doctor based on blood tests showing elevated bilirubin levels.
How does this variant affect chemotherapy?
The variant can reduce the body's ability to clear certain chemotherapy drugs like irinotecan. This can lead to higher levels of the drug in the blood, potentially increasing the risk of side effects like diarrhea or low white blood cell counts.
Should I get tested for this variant?
Genetic testing for this variant is usually only recommended by a doctor if you are about to start a medication that is known to be affected by UGT1A1 activity. It is not typically used as a routine screening tool for the general population.
Sources & further reading
Educational information only, last refreshed 10/2/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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Missense variant corresponding to the functional UGT1A1*27 allele associated with reduced glucuronidation and elevated irinotecan toxicity risk.
Variant allele in UGT1A1 (defining UGT1A1*60 in the promoter region) associated with altered glucuronidation and elevated risk of irinotecan-induced neutropenia and hyperbilirubinemia.
The TT genotype is associated with significantly increased serum bilirubin concentrations in pediatric populations.
Missense alteration associated with reduced glucuronidation capacity and increased susceptibility to irinotecan toxicity and hyperbilirubinemia.
This variant in the UGT1A gene cluster is associated with serum total bilirubin levels and susceptibility to Gilbert syndrome.
Defines the decreased-function UGT1A1*6 missense allele (p.Gly71Arg), widely implicated in East Asian populations in severe irinotecan-induced neutropenia and neonatal hyperbilirubinemia.