MLL's new diagnostic service: UGT1A1 genotyping

We are pleased to inform you that, starting in July 2025, the MLL will offer molecular genetic analysis of the UGT1A1 gene. This analysis will enable the identification of clinically relevant polymorphisms, particularly the UGT1A1*28 and UGT1A1*6 variants, which are important for diagnosing Gilbert syndrome and for understanding drug-induced toxicity (e.g., irinotecan and nilotinib) from a pharmacogenetic perspective.

The UGT1A1 gene codes for an enzyme responsible for glucuronidation of  bilirubin and various drugs. Changes in this gene can lead to reduced enzyme activity, resulting in hyperbilirubinemia (Gilbert syndrome) and an increased risk of drug side effects, particularly in cases of irinotecan or nilotinib administration. Two variants of particular clinical relevance are UGT1A1*28 (a promoter polymorphism) and UGT1A1*6 (a coding single nucleotide polymorphism, or SNP), which, alone or in combination, cause reduced enzyme activity. These variants can therefore contribute to a better risk assessment and adjustment of therapy for certain drugs.

The frequency of UGT1A1 polymorphisms varies by ethnic origin:

• UGT1A1*28: Approximately 30-40% allele frequency in European and African populations. Homozygosity is approximately 10-15%.
• UGT1A1*6: This allele is very rare in European populations, with an allele frequency below 1%. It is significantly more frequent in East Asian populations, with a frequency of 13%-23%. Homozygosity is approximately 5%-10%.
• Compound heterozygosity (*6/*28) is also possible and clinically relevant.

The following cases benefit from genotyping of the UGT1A1 gene:

• Before starting irinotecan chemotherapy
• For planned therapies with nilotinib
• Suspicion of Gilbert syndrome (a diagnostic indication for persistent mild hyperbilirubinemia).

Homozygous or combined heterozygous carriers of the UGT1A1*28 and *6 variants have reduced UGT1A1 enzyme activity. This leads to a slight increase in unconjugated (indirect) bilirubin and may be accompanied by scleral icterus, nonspecific abdominal complaints, loss of appetite, and fatigue, particularly during fasting and after physical exertion. These symptoms are characteristic of Gilbert syndrome, a typically benign but often misdiagnosed metabolic condition.

Irinotecan is a topoisomerase I inhibitor used to treat various tumor entities. Its active metabolite, SN-38, is inactivated in the liver by glucuronidation through the enzyme UGT1A1. Reduced activity of the UGT1A1 enzyme (e.g. in individuals with the UGT1A1*28/*28 or UGT1A1*6/*6 genotypes) can result in severe adverse effects, including neutropenia and diarrhea. In these cases, a dose adjustment is recommended (see the Red Hand Letter from the Federal Institute for Drugs and Medical Devices [BfArM]).

Reduced UGT1A1 activity can lead to decreased bilirubin excretion, increased hyperbilirubinemia, and an elevated risk of adverse effects during nilotinib treatment. Knowing the genotype can help with risk assessment and therapy adjustments. However, there is not yet sufficient research to recommend reducing the dose of nilotinib based on UGT1A1 status.

Analysis of the following polymorphisms is offered by our molecular genetics laboratory:

• UGT1A1 *28 (A(TA)7TAA Promoter variant)
• UGT1A1 *6 (c.211G>A, Gly71Arg)

Testing is carried out applying polymerase chain reaction (PCR) and melting curve analysis. The results are summarized in a medical report that clearly interprets them in a clinical context.