Genetic variations and haplotypes of UDP-glucuronosyltransferase 1A locus in a Korean population

Glucuronidation catalyzed by UDP-glucuronosyltransferases (UGTs) is one of the most important mechanisms for host defense against xenobiotics and endobiotics. Although genetic polymorphisms of several UGT1A isoforms have been reported separately, the haplotypes in all functional exons have not been identified, and little information is available regarding single nucleotide polymorphisms in Koreans. We analyzed genetic polymorphisms in all functional exons of the UGT1A locus by direct sequencing of genomic DNA from 50 healthy Korean subjects, and their haplotypes were inferred from genotype data using an expectation-maximization algorithm. We identified 67 polymorphisms, including three novel single nucleotide polymorphisms, 233C>T in UGT1A1 (T78M), 292C>T in 1A4 (Q98Stop), and 701T>C in 1A7 (I234T). Two amino acid substitutions, 1A4 Q98Stop and 1A7 I234T, were each associated with a decrease of enzymatic activity, whereas UGT1A1 T78M had no significant influence on catalytic function. The frequencies of the known variants in Koreans differed significantly from those reported in other ethnic groups. Haplotype analysis was performed within the polymorphisms in each UGT1A isoform as well as across the isoforms. Based on strong linkage disequilibrium within UGT1A7, between 1A5 and 1A4, and within 1A3, the complex was divided into three blocks, Block 7, Block 5/4, and Block 3. The haplotypes for each block were subsequently determined, revealing a profile that differed from those of other ethnic groups. These results suggest that genetic polymorphisms of the UGT1A locus differ between Koreans and other ethnic populations. Such differences should be considered in pharmacogenetic studies.