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Journal Article

Gilbert syndrome redefined: A complex genetic haplotype influences the regulation of glucuronidation.


Naumann,  Ronald
Max Planck Institute of Molecular Cell Biology and Genetics, Max Planck Society;

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Ehmer, U., Kalthoff, S., Fakundiny, B., Pabst, B., Freiberg, N., Naumann, R., et al. (2012). Gilbert syndrome redefined: A complex genetic haplotype influences the regulation of glucuronidation. Hepatology (Baltimore, Md.), 55(6), 1912-1921.

Cite as: https://hdl.handle.net/21.11116/0000-0001-082E-4
Gilbert syndrome (GS) is characterized by intermittent unconjugated hyperbilirubinemia without structural liver damage affecting about 10% of the white population. In GS the UGT1A1*28 variant reduces bilirubin conjugation by 70% and is associated with irinotecan and protease inhibitor side effects. Aim of this study was to characterize potential in vivo consequences of UGT1A gene variability in GS. Three hundred GS patients (UGT1A1*28 homozygous) and 249 healthy blood donors (HBD) were genotyped for UGT1A (UGT1A1*28, UGT1A3-66 T>C, UGT1A6*3a, UGT1A7*3) and transporter SNPs (SCLO1B1 p.V174A, SCLO1B1 p.N130D, ABCC2 p.I1324I, ABCC2 -24 UTR) using TaqMan-5'-nuclease-assays. A humanized transgenic UGT1A-SNP and corresponding wild-type mouse model were established carrying the GS-associated UGT1A variant haplotype. UGT1A transcript and protein expression, and transcriptional activation were studied in vivo. Homozygous UGT1A1*28 GS individuals were simultaneously homozygous for UGT1A3-66 T>C (91%), UGT1A6*2a (77%), and UGT1A7*3 (77%). Seventy-six percent of GS and only 9% of HBD were homozygous for the variant haplotype spanning 4 UGT1A genes. SCLO1B1 and ABCC2 single nucleotide polymorphisms (SNPs) showed no differences. In transgenic humanized UGT1A SNP and wild-type mice this UGT1A haplotype led to lower UGT1A mRNA expression and UGT1A protein synthesis. UGT1A transcriptional activation by dioxin, phenobarbital and endotoxin was significantly reduced in SNP mice. CONCLUSION: Our data redefine the genetic basis behind GS. In vivo data studying the genotype present in 76% of GS individuals suggest that transcription and transcriptional activation of glucuronidation genes responsible for conjugation and detoxification is directly affected leading to lower responsiveness. This study suggests that GS should be considered as a potential risk factor for drug toxicity. (HEPATOLOGY 2011.).