UGT1A128alleeli

UGT1A128alleeli is a promoter variant of the UGT1A1 gene, commonly referred to as the UGT1A1*28 allele. It involves the addition of an extra TA repeat in the TATA box of the gene’s promoter, changing the sequence from A(TA)6TAA to A(TA)7TAA. This modification reduces transcriptional activity of UGT1A1 and lowers the enzyme’s overall glucuronidation capacity.

The UGT1A1 gene encodes uridine diphosphate-glucuronosyltransferase 1A1, an enzyme in the UDP-glucuronosyltransferase family responsible for conjugating bilirubin and various drugs with glucuronic acid for elimination. The promoter TA repeat polymorphism can thus influence bilirubin handling and the metabolism of certain xenobiotics.

Clinical significance includes an association between UGT1A128alleeli and mild unconjugated hyperbilirubinemia, particularly in individuals who are homozygous or compound heterozygous for the variant, a condition known as Gilbert syndrome. Beyond bilirubin metabolism, the variant affects the pharmacokinetics of irinotecan (CPT-11), because its active metabolite SN-38 is detoxified by UGT1A1. Carriers of the allele may experience higher SN-38 exposure and a greater risk of neutropenia and diarrhea during irinotecan therapy, which has led to genotype-guided dosing considerations in certain guidelines.

Allele frequency varies by ethnicity, with higher prevalence of the UGT1A128alleeli in some populations (notably individuals of African and Caucasian descent) and lower frequencies in others. Other UGT1A1 variants, such as rare or population-specific alleles, can also influence enzyme activity.

See also: Gilbert syndrome, UGT1A1 gene, pharmacogenomics, CPIC guidelines.