Serum bilirubin concentration in healthy adult North-Europeans is strictly controlled by the UGT1A1 TA-repeat variants

PLoS One. 2014 Feb 28;9(2):e90248. doi: 10.1371/journal.pone.0090248. eCollection 2014.

Abstract

The major enzyme responsible for the glucuronidation of bilirubin is the uridine 5'-diphosphoglucose glucuronosyltransferase A1 (UGT1A1) enzyme, and genetic variation in the UGT1A1 gene is reported to influence the bilirubin concentration in the blood. In this study, we have investigated which gene-/haplotype variants may be useful for genetic testing of Gilbert's syndrome. Two groups of samples based on serum bilirubin concentrations were obtained from the Nordic Reference Interval Project Bio-bank and Database (NOBIDA): the 150 individuals with the highest bilirubin (>17.5 µmol/L) and the 150 individuals with normal bilirubin concentrations (<17.5 µmol/L). The individuals were examined for the TA6>TA7 variant in the UGT1A1 promoter and 7 tag-SNPs in an extended promoter region of UGT1A1 (haplotype analysis) and in selected SNPs in candidate genes (SLCO1B3, ABCC2 and NUP153). We found significant odds ratios for high bilirubin level for all the selected UGT1A1 variants. However, in stepwise multivariate logistic regression analysis of all genetic variants together with age, sex, country of origin and fasting time, the repeat variants of UGT1A1 TA6>TA7 and SLCO1B3 rs2117032 T>C were the only variants significantly associated with higher bilirubin concentrations. Most individuals with high bilirubin levels were homozygous for the TA7-repeat (74%) while only 3% were homozygous for the TA7-repeat in individuals with normal bilirubin levels. Among individuals heterozygous for the TA7-repeat, a low frequent UGT1A1-diplotype harboring the rs7564935 G-variant was associated with higher bilirubin levels. In conclusion, our results demonstrate that in testing for Gilbert's syndrome, analyzing for the homozygous TA7/TA7-genotype would be appropriate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Bilirubin / blood*
  • Dinucleotide Repeats*
  • Female
  • Gilbert Disease / blood
  • Gilbert Disease / enzymology
  • Gilbert Disease / ethnology
  • Gilbert Disease / genetics
  • Glucuronosyltransferase / blood
  • Glucuronosyltransferase / genetics*
  • Heterozygote
  • Homozygote
  • Humans
  • Male
  • Middle Aged
  • Multidrug Resistance-Associated Protein 2
  • Organic Anion Transporters, Sodium-Independent / genetics*
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic
  • Scandinavian and Nordic Countries
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • White People

Substances

  • ABCC2 protein, human
  • Multidrug Resistance-Associated Protein 2
  • Organic Anion Transporters, Sodium-Independent
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Bilirubin

Grants and funding

This study has been financed with aid from the South-Eastern Norway Regional Health Authority and a grant from Norsk Fond for Klinisk Kjemi. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.