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 micromol/L (P = .001) with hyperbilirubinemia exceeding 43 micromol/L in 37%. Hyperbilirubinemia over 43 micromol/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 micromol/L) to 41% to 46.1% (43 to >85 micromol/L), and 100% (>85 micromol/L). All six patients with hyperbilirubinemia greater than 85 micromol/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.
Lankisch
Tim O
TO
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Moebius
Ulrike
U
Wehmeier
Michael
M
Behrens
Georg
G
Manns
Michael P
MP
Schmidt
Reinhold E
RE
Strassburg
Christian P
CP
D000328:Adult; D000368:Aged; D000069446:Atazanavir Sulfate; D005260:Female; D014644:Genetic Variation; D005878:Gilbert Disease / Q000150:complications / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics*; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D006239:Haplotypes; D006801:Humans; D006932:Hyperbilirubinemia / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000009:adverse effects* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011725:Pyridines / Q000009:adverse effects* / Q000627:therapeutic use
D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D014453:Glucuronosyltransferase