A Combinatorial Haplotype of the UDP-Glucuronosyltransferase 1A1 Gene (#60-#IB) Increases Total Bilirubin Concentrations in Japanese Volunteers

Abstract

UDP-glucuronosyltransferases (UGTs)are a family of enzymes that glucuronidate many endogenous and exogenous substrates (1). Of the UGT1A gene isoforms, UGT1A1 is primarily responsible for glucuronidation of bilirubin (1). In east Asians, 2 well-known genetic variants, A(TA)6TAA>A(TA)7TAA (allele * 28 , reduced transcription) and G71R (211G>A, allele * 6 , reduced activity), are causative factors for increased plasma bilirubin concentrations in Gilbert syndrome (1). The * 28 allele is almost always linked to the * 60 allele (-3279T>G), with reduced in vitro transcription (2). In a previous study (2) in which we divided UGT1A1 into 2 haplotype blocks (the 5′-flanking region and exon 1 in block 1 and common exons 2 to 5 in block 2), * 60 and * IB (perfectly linked 1813C>T, 1941C>G, and 2042C>G in the 3′-untranslated region in Japanese persons) showed increased total bilirubin concentrations in non-* 28 patients. Because of the small number of patients, however, it was not clear whether bilirubin concentrations were affected by * 60 and * IB acting independently or cooperatively when they were on the same chromosome. To clarify this point, we reinvestigated the associations between the UGT1A1 haplotypes and total bilirubin concentrations in 554 healthy Japanese volunteers. The ethical review boards of the participating institutions approved this study, and informed consent was obtained from all participants. For genotyping of * 60 , * 28 , * 6 , and * IB marker variations, DNA …