Haplotype analysis of UGT1A1 and UGT1A9 gene polymorphisms related to the glucuronidation of SN-38, the active metabolite of irinotecan

Abstract

2085 Background: There are 9 unique UGT1A enzymes with overlapping specificity and tissue-specific expression, which are generated from a single gene by alternative splicing of individual exons 1 with common exons 2–5. The TA repeat polymorphism in UGT1A1and other UGT1A1 variants have been suggested to play a role in increased risk of severe toxicity of irinotecan. In addition to UGT1A1, UGT1A9 enzyme has also been proposed to inactivate SN-38, and a T indel in the 5' untranslated region has been associated with altered gene expression. As UGT1A1-UGT1A9 haplotypes might have a different phenotypic effect compared to single variants, we sought to determine the haplotype map of UGT1A1 and UGT1A9functional variants. Asian (n=150) and Caucasian (n=66) samples were used to evaluate interethnic differences in haplotype structure. Methods: DNA samples were genotyped for variants in UGT1A9 (-11810T/9T) and UGT1A1 [-3279G>T, -3156G>A, -53TA5–8, 211G>A, 686C>A]. Results: In both populations, significant linkage disequilibrium (LD) was present among all variants (p<0.05) except between -11810T/9T and 686C>A. Stronger LD was found in Caucasians compared to Asians. In Asians, 13 haplotypes (1–13) were found, 8 of them being present in Caucasians. In Asians, common haplotypes (q>0.10) were 10TG6GC (1, q=0.44), 9GG6GC (2, q=0.22), and 9TG6AC (3, q=0.12), and common diplotypes were 1,1 (0.19), 1,2 (0.18), and 1,3 (0.13). In Caucasians, 211G>A was invariant and one 686C>A heterozygote was found; common haplotypes were 10TG6GC (1, q=0.35), 9GA7GC (9, q=0.28), 9TG6GC (4, q=0.19), and 9GG6GC (2, q=0.10); common diplotypes were 1,9 (0.20), 1,4 (0.17), 1,1 (0.12), and 9,9 (0.11). Significantly different haplotype frequencies were observed between Asians and Caucasians (chi-square 97.4, p<0.0001). Conclusions: The haplotype map of UGT1A1 and UGT1A9is different between Asians and Caucasians. These results provide the knowledge basis for the correct design of prospective clinical trials of irinotecan (and other UGT1A substrates) pharmacogenetics with respect to UGT1A1 andUGT1A9in patients of Asian and Caucasian ethnic background. No significant financial relationships to disclose.