Comprehensive UGT1A1 Genotyping in a Japanese Population by Pyrosequencing

Glucuronidation, catalyzed by UDP-glucuronosyltransferases (UGTs), is important in the detoxification and enhanced elimination of a large number of endogenous and exogenous substrates. The human UGT1A gene complex contains at least nine variations of exon 1, common exons 2–5, and a single exon 1 splices to exons 2–5 (1). Of the UGT1A isoforms, UGT1A1 is primarily responsible for the glucuronidation of bilirubin in the human liver and can also conjugate phenols, anthraquinones, flavonoids, and a variety of therapeutic drugs and their metabolites (e.g., SN-38, an active irinotecan metabolite) (2)(3). Several functional polymorphisms in UGT1A1 are associated with reduced bilirubin glucuronidation activity and cause hyperbilirubinemia (Gilbert and Crigler–Najjar syndromes). UGT1A1 TATA box variants [A(TA)6TAA>A(TA)5/7/8TAA] are associated with enhanced [(TA)5] or reduced [(TA)7/8] UGT1A1 transcription (4). Among them, the (TA)6 and (TA)7 repeats have been reported in Asians. The variant (TA)7 is associated with reduced glucuronidation of SN-38 and bilirubin, as well as the pathogenesis of Gilbert syndrome (5). In addition, a T-to-G substitution at nucleotide −3279 (A of the translational start codon in GenBank accession no. AF297093.1 is nucleotide number 1) in the UGT1A1 phenobarbital-responsive enhancer module reduces transcriptional activity (6). The most common nonsynonymous single-nucleotide polymorphism (SNP) (211G>A) that causes an amino acid alteration (glycine to arginine at codon 71) is found in Asian populations at frequencies of 13–23% (7)(8). The 686C>A (P229Q) variation in the Taiwanese has a frequency of 2.8% (8). Also associated with Gilbert syndrome are 211G>A (G71R) and 686C>A (P229Q). Rare in Japanese and Taiwanese patients is 1456T>G (Y486D), which is associated with the more severe type II Crigler–Najjar syndrome (8)(9). Our previous study demonstrated that …