Genetic variation in bilirubin UDP-glucuronosyltransferase gene promoter and Gilbertʹs syndrome

Background The genetic basis of Gilbertʹs syndrome is ill-defined. This common mild hyperbilirubinaemia sometimes presents as an intermittent jaundice. A reduced hepatic bilirubin UDP-glucuronosyltransferase (UGT) is associated with this syndrome. We have examined variation in the gene encoding the UGT1*1 enzyme and serum bilirubin levels in a Scottish population. Methods Blood was collected from 12 patients with confirmed or suspected Gilbertʹs syndrome, from 6 members of a family with 4 Gilbert members, and from 77 non-smoking, alcohol-free, drug-free volunteers recruited from the staff of a teaching hospital in Dundee. Polymerase chain reaction amplification was used to examine sequence variation of the promoter upstream of the UGT1*1 exon I. Genotypes were assigned as follows: 6/6 (homozygous for a common allele bearing the sequence [TA]6TAA), 7/7 (homozygous for a rarer allele with the sequence [TA]7TAA), and 6/7 (heterozygous with one of each allele). Findings Individuals in the population with the 7/7 genotype had significantly higher bilirubin concentrations than those who had the 6/7 or 6/6 genotype. 14 volunteers underwent a 24 h fasting test to see if they had Gilbertʹs syndrome, and all four positives had the 7/7 genotype. One confirmed Gilbertʹs patient, two recurrent jaundice patients (with suspected Gilbertʹs syndrome), and nine clinically diagnosed cases had the 7/7 genotype. Segregation of the 7/7 genotype with the Gilbert phenotype was also demonstrated in the family with four affected members. The frequency of the 7/7 genotype in this eastern Scottish population was 10-13%. Interpretation In a healthy population there was an association between variation in bilirubin concentration and a mutation within the gene encoding the enzyme bilirubin UGT. This and other findings suggest the existence of a mild and a more severe form of Gilbertʹs syndrome, depending on whether the gene defect lies in the promoter sequence upstream of UGT1*I exon I, as here (mild), or in the coding sequence (severe) of the gene.