Genetic Polymorphisms of UGT 1A1*28 in the TATA-box Promoter Region of Bilirubin Uridinediphosphate-glucuronosyltransferase Gene in Children with Gilbert’s Syndrome

Overview

Aim:
Mutations in the promoter and coding region of the bilirubin UDP-glucuronosyltransferase gene (UGT 1A1) are known to be associated with Gilbert’s syndrome (GS), although the molecular epidemiology and basis for this syndrome in children has yet to be clarified. Authors aimed at evaluating the frequency of UGT 1A1*28 polymorphisms in the promoter region of the UDP-glucuronosyltransferase gene (the TATA-box mutation), and their clinical implications in GS.

Methods:
Analyses of the TATA-box mutations were performed in 53 patients with GS and 27 controls using PCR amplification.

Results:
Genotypes were assigned as follows: TA(6)/TA(6) (homozygous for a normal allele bearing the sequence [TA](6)TAA), TA(7)/TA(7) (homozygous for an mutated allele with the sequence [TA](7)/TAA), and TA(6)/TA(7) (heterozygous with one on each allele). Male patients (79.2%) tended to have GS more frequently than female patients (20.8%). There were significant differences in mean serum bilirubin levels between GS patients and controls (p < 0.0001). Of the 53 GS patients, 94.3% had homozygous TA(7)/TA(7) genotype, and 5.7 % had TA(6)/TA(7). Of 27 controls, the frequency of the abnormal allele was 51.9 %, one patient (3.8%) had TA(7)/TA(7), 13 had TA(6)/TA(7) (48.1%), and 13 (48.1%) had normal genotype TA(6)/TA(6). Calculated frequency of TA(7)/TA(7) genotype is 8% in the pediatric population.

Conclusion:
TATA-box mutations have a significant effect on serum bilirubin levels. Homozygous TA(7)/TA(7)-box variant of the promoter region of UGT 1A1*28 gene is strongly associated with GS predominantly in male Czech pediatric patients. These results have clear implications for clinical practice in children with disorders of bilirubin metabolism.

Key words:
Gilbert’s syndrome, UGT 1A1*28 polymorphisms, hyperbilirubinemia, TATA-box mutations