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Received for publication August 10, 2004.
Revised November 15, 2004.
Accepted for publication November 23, 2004.
Ethnic differences in genetic polymorphisms in UDP-glycuronosyltransferase 1A1 (UGT1A1) were investigated among African-Americans, Caucasians and Japanese using samples obtained from 150 individuals for each population. Genotyping of -3279T>G in the PBREM, TA repeats in the TATA box, 211G>A (G71R) and 686C>A (P229Q) in exon 1, and three SNPs (1813C>T, 1941C>G and 2042C>G) in the 3'-untranslated region in exon 5 was performed. Eight haplotypes of Block 1 (exon 1 and its 5'-flanking region) harboring the first four variations were assigned to each individual. The dominant haplotype for African-Americans was *28b (-3279G;TA7;211G;686C) (0.446), while that for the Japanese was *1a (-3279T;TA6;211G;686C) (0.610). Frequencies of the two haplotypes *1a and *28b were comparable in Caucasians. Haplotype *6a (-3279T;TA6;211A;686C) was characteristic of the Japanese, whereas haplotypes *36b and *37b (-3279T;TA5 and TA8;211G;686C) were found mostly in African-Americans. Although the three SNPs in Block 2 (exons 2-5) were in complete linkage in the Japanese, they were not completely linked in African-Americans or Caucasians. These differences in haplotype distribution patterns among the three populations suggest the possibility of ethnic differences in toxicity profiles of drugs detoxicated by UGT1A1. A novel SNP, 686C>T (P229L), was found in an African-American. The intrinsic clearance of SN-38 by P229L UGT1A1 expressed in COS-1 cells was about 3% of the wild type. The results of Western blotting and real-time RT-PCR suggest that the low glucuronidation activity of the variant was partly due to its low stability. The variation 686C>T may cause high toxicity during CPT-11 therapy or hyperbilirubinemia in patients.
Key words:
ethnic differences, genetic polymorphism, glucuronidation, UDP glucuronyltransferases
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