Haplotype structures of the UGT1A gene complex in a Japanese population

Abstract

Genetic polymorphisms of UDP-glucuronosyltransferases (UGTs) are involved in individual and ethnic differences in drug metabolism. To reveal cooccurrence of the UGT1A polymorphisms, we first analyzed haplotype structures of the entire UGT1A gene complex using the polymorphisms from 196 Japanese subjects. Based on strong linkage disequilibrium between UGT1A8 and 1A10, among 1A9, 1A7, and 1A6, and between 1A3 and 1A1, the complex was divided into five blocks, Block 8/10, Block 9/6, Block 4, Block 3/1, and Block C, and the haplotypes for each block were subsequently determined/inferred. Second, using pyrosequencing or direct sequencing, additional 105 subjects were genotyped for 41 functionally tagged polymorphisms. The data from 301 subjects confirmed the robustness of block partitioning, but several linkages among the haplotypes with functional changes were found across the blocks. Thus, important haplotypes and their linkages were identified among the UGT1A gene blocks (and segments), which should be considered in pharmacogenetic studies.

Close Association of UGT1A9 IVS1+399C>T with UGT1A1*28, *6, or *60 Haplotype and Its Apparent Influence on 7-Ethyl-10-hydroxycamptothecin (SN-38) Glucuronidation in Japanese

“…Genomic DNA was extracted from whole blood of 177 irinotecan-administered patients (Saeki et al, 2006). UGT1A9 IVS1ϩ399CϾT (rs2741049) was genotyped using the TaqMan SNP Genotyping Assay kit (C_9096281_10) according to the manufacturer's instructions (Applied Biosystems, Foster City, CA).…”

“…Allele frequencies have been reported for *28 (0.09 -0.13), *6 (0.15-0.19), and *60 (0.26 -0.32) in Japanese and Chinese populations and for *28 (0.30 -0.39), *6 (ϳ0), and *60 (0.44 -0.55) in whites . In a previous study, in the Japanese population, we defined haplotype *28 as the haplotype harboring the *28 allele, haplotype *6 as that harboring the*6 allele, and haplotype *60 as that harboring the *60 allele (and without the *28 or *6 allele) (Sai et al, 2004;Saeki et al, 2006). Note that most of the *28 haplotypes concurrently harbored the *60 alleles, and that the *28 and *6 alleles were exclusively present on the different chromosomes (Sai et al, 2004;Saeki et al, 2006).…”

“…In a previous study, in the Japanese population, we defined haplotype *28 as the haplotype harboring the *28 allele, haplotype *6 as that harboring the*6 allele, and haplotype *60 as that harboring the *60 allele (and without the *28 or *6 allele) (Sai et al, 2004;Saeki et al, 2006). Note that most of the *28 haplotypes concurrently harbored the *60 alleles, and that the *28 and *6 alleles were exclusively present on the different chromosomes (Sai et al, 2004;Saeki et al, 2006). We have also revealed that the haplotype *28, *6, or *60 was associated with reduced SN-38 glucuronide (SN-38G)/SN-38 area under concentration-time curve (AUC) ratios, an in vivo parameter for UGT1A activity (Minami et al, 2007).…”

UGT1A1*28 and *6 polymorphisms and nilotinib-induced unconjugated hyperbilirubinemia in a Japanese patient with chronic myelogenous leukemia

“…The allele mutation UGT1A1*28 occurs at frequencies up to 40 % in the Caucasian population and is seen in the Japanese population at lower rates (9-13 %). On the other hand, the UGT1A1*6 allele, which is extremely rare in Caucasians, is more frequent than the UGT1A1*28 allele in Japanese people [8][9][10]. Taking account of the frequency of UGT1A1 polymorphisms in the Japanese population, we might have to consider the influence of UGT1A1*6 polymorphism on nilotinib-induced unconjugated hyperbilirubinemia.…”

Study on the association of UGT1A9 gene c.98T>C polymorphism and mycophenolic acid plasma levels in renal transplant patients

“…This SNP was not detected in the population study of Mazidi et al (2013). The lack of detection of some of these mutations was assessed in Japanese and Chinese populations in which none of these SNPs were observed (Saeki et al, 2006;Kagaya et al, 2007;Jiao et al, 2008).…”