GENETIC-VARIATION IN BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE GENE PROMOTER AND GILBERTS-SYNDROME

Background The genetic basis of Gilbert's syndrome is ill-defined. Thi s common mild hyperbilirubinaemia sometimes presents as an intermitten t jaundice, A reduced hepatic bilirubin UDP-glucuronosyltransferase (U GT) is associated with this syndrome, We have examined variation in th e gene encoding the UGT11 enzyme and serum bilirubin levels in a Scot tish population. Methods Blood was collected from 12 patients with con firmed or suspected Gilbert's syndrome, from 6 members of a family wit h 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 v ariation of the promoter upstream of the UGT11 exon I, Genotypes were assigned as follows: 6/6 (homozygous for a common allele bearing the sequence [TA](6)TAA), 7/7 (homozygous for a rarer allele with the sequ ence [TA](7)TAA), and 6/7 (heterozygous with one of each allele). Find ings Individuals in the population with the 7/7 genotype had significa ntly 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 Gilbert's syndrome, and all four positives had the 7/7 genotype. O ne confirmed Gilbert's patient, two recurrent jaundice patients (with suspected Gilbert's syndrome), and nine clinically diagnosed cases had the 7/7 genotype. Segregation of the 7/7 genotype with the Gilbert ph enotype was also demonstrated in the family with four affected members . The frequency of the 7/7 genotype in this eastern Scottish populatio n was 10-13%. Interpretation In a healthy population there was an asso ciation between;variation in bilirubin concentration and a mutation wi thin the gene encoding the enzyme bilirubin UGT, This and other findin gs suggest the existence of a mild and a more severe form of Gilbert's syndrome, depending on whether the gene defect lies in the promoter s equence upstream of UGT1I exon I, as here (mild), or in the coding se quence (severe) of the gene.