Serum Bilirubin Concentration in Healthy Adult North-Europeans Is Strictly Controlled by the UGT1A1 TA-Repeat Variants

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.

Metabolic abnormalities in Williams–Beuren syndrome

“…The penetrance is incomplete and varies depending on the criteria used to define the phenotype, being around 40% for the homozygous hypomorphic allele. Genotype frequencies at UGT1A1 in our WBS cohort were similar to those reported in the Spanish population,45 and bilirubin levels correlated with UGT1A1 genotype, as previously reported 24 46 47. No association was found with SLCO1B1, 18 coding for an hepatic transporter in the basolateral membrane of hepatocytes for bilirubin 18 48.…”

Bilirubin Is Inversely Associated With Cardiovascular Disease Among HIV‐Positive and HIV‐Negative Individuals in VACS (Veterans Aging Cohort Study)

“…24 In particular, those homozygous for the UGT1A1*28 allele had one third of the risk of coronary heart disease than those who were not homozygotes in the Framingham Heart Study. 25 Although the (TA)-repeat variation in the UGT1A1 gene is the main genetic factor for determining bilirubin concentrations, the penetrance ranges from 1% to 67%, 26 further confounding the genetic association, protein expression, and CVD outcomes. Genetic association studies have not conclusively found an association between the (TA)repeat variation or a causal relationship between bilirubin and CVD outcomes; however, a causal relationship cannot be excluded on the basis of these studies.…”

Parenteral bilirubin in healthy volunteers: a reintroduction in translational research

“…Notably, the vast majority of reports on the parenteral use of bilirubin have not mentioned any side effect related to its infusion. Several of these reports explicitly mentioned the absence of side effects, covering a total of 278 bilirubin infusions with plasma concentrations up to 150 μmol l −1 .…”

“…Third, the clearance of bilirubin demonstrates a significant inter‐individual variability which is related to several genetic polymorphisms . Most common is the Gilbert syndrome, which is due to a TA‐insertion in the UGT1A1 promotor region and accompanied by a significantly reduced glucuronidation activity to approximately 30% of normal .…”