Haplotypes of variants in the UDP-glucuronosyltransferase1A9 and 1A1 genes

Abstract

Nine different functional UGT1A enzymes are generated from a single UGT1A gene by alternative splicing, with each enzyme having a unique exon 1. SN-38, the active metabolite of the anticancer agent irinotecan, is metabolized by both UGT1A1 and UGT1A9. We aim to characterize the UGT1A9-UGT1A1 haplotypes in Asians and Caucasians and gain insights on their functional consequences. Asian and Caucasian individuals were genotyped for UGT1A1 and UGT1A9 variants. A higher frequency of the UGT1A9 -118T10 allele was observed in Asians compared to Caucasians, while the -275T>A and -2152C>T variants were relatively uncommon in Caucasians and not found in Asians. The strongest linkage disequilibrium (LD) was observed between the UGT1A1 -53 and -3156 and between the UGT1A9 -275 and -2152 loci. Lower LD was observed between the -118 UGT1A9 variant and the UGT1A1 variants. Fourteen UGT1A9-UGT1A1 haplotypes were found in Asians, seven of them found to be shared by both populations. Common UGT1A9-UGT1A1 diplotypes were defined, and a difference was observed across the SN-38 glucuronidation rates in Caucasian livers stratified by diplotypes. This study for the first time described common UGT1A9-UGT1A1 haplotypes, highlighting important ethnic differences between Asians and Caucasians. If the functional effect of these haplotypes can be confirmed, this haplotypic information would be applicable to the correct design of prospective clinical studies of irinotecan, as well as of other drugs primarily metabolized by both UGT1A1 and UGT1A9.