Background:  Atazanavir (ATV) can cause severe jaundice in some patients, particularly those with Gilbert’s disease. Gilbert’s disease is characterized by a TATA box polymorphism in the human bilirubin-UGT gene on chromosome 2 (UGT1A1*28). Based on the hypothesis of genetically determined metabolic risk factors and to test the involvement of these functional single nucleotide polymorphisms (SNP) in ATV toxicity, we performed a UGT1A gene haplotype analysis in ATV-treated HIV⁺ patients, including not only UGT1A1*28 but also UGT1A3-66, UGT1A7 129/131, and UGT1A7-57. The hypothesis was based on ATV’s ability to inhibit enzymatic glucuronidation activity, potentially demasking inbred variants of UGT-mediated metabolism.

Methods:  SNP-detection of UGT1A1*28, UGT1A3-66, UGT1A7 129/131, and UGT1A7-57 was performed by DNA sequencing and Taqman 5’-nuclease assays in 106 ATV-treated patients and 104 healthy blood donors.

Results:  Homozygous allelic variants and allelic frequencies of UGT1A3 and UGT1A7 were significantly higher in the ATV-treated group compared to healthy blood donors (p <0.0006 and p <0.02, respectively). A significantly higher rate of homozygous allelic variants of UGT1A1*28 was found in patients with grade 3 and 4 hyperbilirubinemia (p <0.00005) compared to healthy blood donors. Of all patients, 76% with allelic variants of UGT1A1, UGT1A3, and UGT1A7 showed grade 3 or 4 hyperbilirubinemia. In addition, all patients with grade 4 hyperbilirubinemia (n = 6) simultaneously carried the homozygous allelic variants of UGT1A1, UGT1A3, and UGT1A7, indicating the presence of a variant UGT1A haplotype in these patients.

Conclusions:  Gilbert’s disease–associated jaundice in ATV-treated patients is a phenotype that is associated with a novel UGT1A gene haplotype encompassing 4 genetic variants with altered glucuronidation activity of the affected genes. In normal individuals these variants do not occur in linkage dysequilibrium. Our analysis demasks a genetic predisposition linked to glucuronidation with additional consequences in drug treatment with compounds specifically glucuronidated by the involved UGT1A genes. The identified UGT1A1-1A3-1A7 haplotype of 4 individual single-nucleotide polymorphisms is inherited on a single allele and a significant predictor of ATV-induced hyperbilirubinemia beyond the suspected UGT1A1*28 variant. Detection of variants at the UGT1A gene locus is an attractive and potentially powerful pharmacogenetic tool for the prediction and identification of drug-associated toxicity.