title: Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome.
abstract: BACKGROUND
  The genetic basis of Gilbert's syndrome is ill-defined. This common mild hyperbilirubinaemia sometimes presents as an intermittent jaundice. A reduced hepatic bilirubin UPD- 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 Gilbert's 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](6)TAA), 7/7 (homozygous for a rarer allele with the sequence [TA](7)TAA), and 6/7 (heterozygous with one of each allele).
  
  
  RESULTS
  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 Gilbert's syndrome, and all four positives had the 7/7 genotype. One 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 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%.
  
  
  CONCLUSIONS
  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 Gilbert's 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.
authors.affiliation: Department of Biochemical Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: G
authors.initials: G
authors.lastname: Monaghan
authors.forename: M
authors.initials: M
authors.lastname: Ryan
authors.forename: R
authors.initials: R
authors.lastname: Seddon
authors.forename: R
authors.initials: R
authors.lastname: Hume
authors.forename: B
authors.initials: B
authors.lastname: Burchell
mesh_terms: D000328:Adult; D000483:Alleles; D001483:Base Sequence; D001663:Bilirubin / Q000097:blood / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005878:Gilbert Disease / Q000175:diagnosis / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012606:Scotland
chemical_list: D014453:Glucuronosyltransferase; D001663:Bilirubin