Journal of hepatology · 2009
Gilbert's syndrome and hyperbilirubinemia in protease inhibitor therapy--an extended haplotype of genetic variants increases risk in indinavir treatment.
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Lankisch Tim O, Behrens Georg, Ehmer Ursula, Möbius Ulrike, Rockstroh Juergen, Wehmeier Michael, Kalthoff Sandra, Freiberg Nicole, Manns Michael P, Schmidt Reinhold E, Strassburg Christian P
Аннотация
BACKGROUND/AIMS: Gilbert's syndrome is a frequent genetic conjugation abnormality associated with adverse drug effects. Genetic UDP glucuronosyltransferase (UGT)1A gene variants can influence gene transcription, inducibility and glucuronidation activity. Protease inhibitors used in human immunodeficiency virus (HIV) infection and chronic viral hepatitis can inhibit UGTs. Indinavir (IDV) can lead to hyperbilirubinemia in Gilbert's syndrome (UGT1A1*28), which does not explain interindividual severity differences and may thus involve additional UGT1A variants.
METHODS: One hundred and twenty-five HIV patients receiving IDV and 427 healthy blood donors were genotyped for the presence of UGT1A1*28, UGT1A3 -66T/C, UGT1A7 -57T/G, UGT1A7(N129K/R131K) using Taqman 5' nuclease assays.
RESULTS: Hyperbilirubinemia was observed in 42%. UGT1A1*28 frequencies did not differ between HIV patients and controls but were significantly higher in hyperbilirubinemic patients. The frequency of homozygous carriers of the 4 UGT1A marker haplotype increased with hyperbilirubinemia affecting all patients with bilirubin levels >85 micromol/l.
CONCLUSIONS: In IDV treatment the risk of severe hyperbilirubinemia is associated with genetic variants of the UGT1A3 and UGT1A7 genes in addition to Gilbert's syndrome (UGT1A1*28). This haplotype is a useful predictor of protease inhibitor-induced side effects.
METHODS: One hundred and twenty-five HIV patients receiving IDV and 427 healthy blood donors were genotyped for the presence of UGT1A1*28, UGT1A3 -66T/C, UGT1A7 -57T/G, UGT1A7(N129K/R131K) using Taqman 5' nuclease assays.
RESULTS: Hyperbilirubinemia was observed in 42%. UGT1A1*28 frequencies did not differ between HIV patients and controls but were significantly higher in hyperbilirubinemic patients. The frequency of homozygous carriers of the 4 UGT1A marker haplotype increased with hyperbilirubinemia affecting all patients with bilirubin levels >85 micromol/l.
CONCLUSIONS: In IDV treatment the risk of severe hyperbilirubinemia is associated with genetic variants of the UGT1A3 and UGT1A7 genes in addition to Gilbert's syndrome (UGT1A1*28). This haplotype is a useful predictor of protease inhibitor-induced side effects.