The Polymorphism C.-3279TG in the Phenobarbital-Responsive Enhancer Module of the Bilirubin Udp-Glucuronosyltransferase Gene is Associated with Gilbert Syndrome (Technical Briefs‪)‬

Hepatic glucuronization of water-insoluble bilirubin is catalyzed by isoenzyme 1A1 of UDP-glucuronosyltransferase (UGT1A1), which is essential for efficient biliary excretion of bilirubin. Mild hyperbilirubinemia, usually 50 [micro]mol/L, is associated with Gilbert syndrome (GS) and is thought to reflect a small reduction in UGT1A1 activity (1,2). The main cause of GS in all studied populations is a TA insertion in the repetitive TATA box of the gene promoter (3-6), which usually consists of 6 repeats. This [(TA).sub.7] allele is extremely common, occurring with an estimated frequency of 38.7% in the white population and 16% in the Asian population (7). In persons with African ancestry, the number of alleles carrying 7 or more repeats is reported to be 49.5% (7). On the basis of the frequencies observed in Caucasians in several studies of smaller series, Beutler et al. (7) calculated a homozygosity frequency of 15%. This predicted value is higher than that in patients with a clinical diagnosis of GS, suggesting incomplete penetrance of the (TA), allele. Moreover, the fact that some GS patients are neither homozygous for the [(TA).sub.7] allele nor have other UGT1A1 genetic deficits points toward the existence of other inherited or acquired factors affecting bilirubin metabolism. Phenobarbital treatment for hyperbilirubinemia increases UGT1A1 activity in the liver via a phenobarbital-responsive enhancer sequence with 3 potential nuclear receptor (NR) motifs separated by ~90 bases (8). From the 5'end, these motifs are named NR4, gtNR1, and NR3. Alterations in this region could be related to hyperbilirubinemia (8). A polymorphism (c.-3279TG) located in the NR3 motif is associated with a decrease in transcriptional activity, to ~62% of wild type (9). This polymorphism was found in patients with GS and the [(TA).sub.7] allele (9,10). More recently, a similar cooperative effect has been observed in cancer patients showing severe irinotecan toxicity (11).