Haplotype structure of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene and its relationship to serum total bilirubin concentration in a male Korean population.

Abstract

UDP-glucuronosyltransferase 1A1 (UGT1A1) is the key enzyme for bilirubin conjugation. Defects in this enzyme can cause a nonhemolytic unconjugated hyperbilirubinemia, such as Crigler–Najjar syndrome type 1 (CN1) and 2 (CN2) and Gilbert syndrome (GS). In 1991, the cDNA of the human UGT1A1 gene was cloned, and this led to the identification of genetic defects in patients with CN1, CN2, and GS (1)(2)(3). It was shown that homozygous or compound heterozygous mutations of the UGT1A1 gene can lead to these inheritable unconjugated hyperbilirubinemias, and >30 variants have been identified (4)(5). In GS, a TATAA box variant [A(TA)6TAA>A(TA)7TAA] in the promoter region of the UGT1A1 gene has been reported in Caucasian populations, and several polymorphisms in the coding region, including 211G>A (G71R), have been reported to have similar associations with GS in Japanese populations (6)(7)(8). Recently, Sugatani et al. (9) identified a T-to-G substitution in the phenobarbital-responsive enhancer module 3279 bp upstream from the UGT1A1 gene. They suggested that the −3279T>G polymorphism could be another risk factor for the development of mild hyperbilirubinemia Presumably, different combinations of the polymorphisms (haplotypes) in the UGT1A1 gene associated with GS or mild hyperbilirubinemia might produce a variety of serum total bilirubin (T-Bil) concentrations. Because these polymorphisms in the UGT1A1 gene lie in a relatively small region (Fig. 1A⇓ ), a certain extent of linkage disequilibrium (LD) among these polymorphisms is expected. Therefore, haplotype analysis is more reasonable than association analysis using any single polymorphism to reveal the genetic background of an increased serum T-Bil concentration. We analyzed the haplotype structure of the UGT1A1 gene and investigated its relationship to the serum T-Bil concentration in healthy Korean males. The study participants were 324 healthy Korean males [mean (SD) age, 49.8 …