OBJECTIVETo analyze potential mutations of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in patients with unconjugated hyperbilirubinemia, and to explore the correlation between the mutations and total serum bilirubin levels.

METHODSGenomic DNA was extracted from peripheral blood samples of patients. Coding sequence and promoter region of the UGT1A1 gene were amplified. Mutations were identified through DNA sequencing.

RESULTSMutations of the UGT1A1 gene were found in 46 out of 61 patients with unconjugated hyperbilirubinemia. Five types of mutations were detected, with a decreasing order of 211G>A, TA insertion in the TATAA promoter element, 686C>A, 1091C>T and 1352C>T. Compared with those carrying a single homozygous mutation or compound heterozygous mutations, total serum bilirubin was higher in those carrying a homozygous mutation in combination with other heterozygous mutations (P< 0.05). Based on the UGT1A1 gene mutations and level of total serum bilirubin, 44 patients were diagnosed with Gilbert syndrome, and 2 were diagnosed with Crigler-Najjar syndrome type 2.

CONCLUSIONThe level of total serum bilirubin is correlated with the number of UGT1A1 gene mutations as well as their heterozygous or homozygous status.

Adolescent ; Adult ; Aged ; Base Sequence ; Bilirubin ; blood ; Case-Control Studies ; DNA Mutational Analysis ; Female ; Glucuronosyltransferase ; genetics ; metabolism ; Heterozygote ; Homozygote ; Humans ; Hyperbilirubinemia ; enzymology ; genetics ; metabolism ; Male ; Middle Aged ; Molecular Sequence Data ; Young Adult

Hyperbilirubinemia is frequently observed in Caucasian HIV patients treated with atazanavir. UDP-glucuronosyltransferase 1A1 polymorphism, UGT1A1*28, which is associated with atazanavir-induced hyperbilirubinemia, is less common in Asians than in Caucasians. However, little is known about the incidence of atazanavir-associated hyperbilirubinemia in Asian populations. Our objective was to investigate the incidence of and tolerability of atazanavir-associated hyperbilirubinemia in Korean HIV patients. The prevalence and cumulative incidence of atazanavir-associated hyperbilirubinemia and UGT1A1*28 allele frequency was investigated in 190 Korean HIV-infected patients treated with atazanavir 400 mg per day. The UGT1A1*28 were examined by direct sequencing of DNA from peripheral whole blood. The UGT1A1*28 allele frequency was 11%. The cumulative incidence of any grade of hyperbilirubinemia was 77%, 89%, 98%, and 100%, at 3, 12, 24, and 30 months, respectively. The cumulative incidence of severe (grade 3-4) hyperbilirubinemia was 21%, 41%, 66%, and 75%, at 3, 12, 24, and 30 months, respectively. However, the point prevalence of severe hyperbilirubinemia did not increase with time and remained around 25%. Our data suggest that atazanavir-associated hyperbilirubinemia is common but transient in a population with low UGT1A1*28 allele frequency.
Adult ; Alleles ; Anti-HIV Agents/*adverse effects/therapeutic use ; Asian Continental Ancestry Group/*genetics ; Female ; Follow-Up Studies ; Gene Frequency ; Glucuronosyltransferase/blood/*genetics ; HIV Infections/complications/*drug therapy ; Humans ; Hyperbilirubinemia/complications/*epidemiology/genetics ; Incidence ; Male ; Middle Aged ; Oligopeptides/*adverse effects/therapeutic use ; Promoter Regions, Genetic ; Pyridines/*adverse effects/therapeutic use ; Republic of Korea