Gilbert's disease and atazanavir: From phenotype to UDP‐glucuronosyltransferase haplotype

Gilbert's disease leads to intermittent non‐hemolytic hyperbilirubinemia by a reduction of hepatic bilirubin glucuronidation associated with the presence of the UDP‐glucuronosyltransferase (UGT) 1A1*28 polymorphism. It is considered benign because it does not result in hepatocellular damage. However, pharmacogenetic analyses have linked UGT1A1*28 to drug toxicity and cancer predisposition. The protease inhibitor atazanavir (ATV) is an inhibitor of hepatic UGT activity leading to hyperbilirubinemia in individual patients. Whether this is linked specifically to UGT1A1*28 or to more complex variants influencing glucuronidation is unclear. One hundred and six ATV‐treated patients were characterized and genotyped for UGT1A1*28, the UGT1A3 (‐66C) and UGT1A7 (‐57G) promoter variants, and UGT1A7 129K/131K . ATV treatment increased median bilirubin levels from 10 to 41 μmol/L ( P = .001) with hyperbilirubinemia exceeding 43 μmol/L in 37%. Hyperbilirubinemia over 43 μmol/L was significantly associated not only with UGT1A1*28 but also with UGT1A3‐66C, UGT1A7‐57G, and UGT1A7 129K/131K , although these variants do not naturally occur in linkage dysequilibrium in blood donors. Homozygous combinations of UGT1A1*28 with the other variants increased from 7.4% (normal bilirubin to 42 μmol/L) to 41% to 46.1% (43 to >85 μmol/L), and 100% (>85 μmol/L). All six patients with hyperbilirubinemia greater than 85 μmol/L were homozygous for all four variants identifying a haplotype inherited on a single allele. In conclusion , the genetic variant associated with Gilbert's disease is identified as part of a haplotype of four UGT1A variants spanning three genes at the UGT1A gene locus. This haplotype predisposes to hyperbilirubinemia in ATV treatment and may have an additional role as a pharmacogenomic risk factor for drug therapy. (H EPATOLOGY 2006;44:1324–1332.)