Comprehensive Variant Screening of the UGT Gene Family

Abstract

PurposeUGT1A1, UGT2B7, and UGT2B15 are well-known pharmacogenes that belong to the uridine diphosphate glucuronyltransferase gene family. For personalized drug treatment, it is important to study differences in the frequency of core markers across various ethnic groups. Accordingly, we screened single nucleotide polymorphisms (SNPs) of these three genes and analyzed differences in their frequency among five ethnic groups, as well as attempted to predict the function of novel SNPs.Materials and MethodsWe directly sequenced 288 subjects consisting of 96 Korean, 48 Japanese, 48 Han Chinese, 48 African American, and 48 European American subjects. Subsequently, we analyzed genetic variability, linkage disequilibrium (LD) structures and ethnic differences for each gene. We also conducted in silico analysis to predict the function of novel SNPs.ResultsA total of 87 SNPs were detected, with seven pharmacogenetic core SNPs and 31 novel SNPs. We observed that the frequencies of UGT1A1 *6 (rs4148323), UGT1A1 *60 (rs4124874), UGT1A1 *93 (rs10929302), UGT2B7 *2 (rs7439366), a part of UGT2B7 *3 (rs12233719), and UGT2B15 *2 (rs1902023) were different between Asian and other ethnic groups. Additional in silico analysis results showed that two novel promoter SNPs of UGT1A1 -690G>A and -689A>C were found to potentially change transcription factor binding sites. Moreover, 673G>A (UGT2B7), 2552T>C, and 23269C>T (both SNPs from UGT2B15) changed amino acid properties, which could cause structural deformation.ConclusionFindings from the present study would be valuable for further studies on pharmacogenetic studies of personalized medicine and drug response.

Simulations of Valproate Doses Based on an External Evaluation of Pediatric Population Pharmacokinetic Models

“…7,25,26,28 Interethnic variability in cytochrome P450 and Uridine Glucuronosyltransferases allele frequencies have been reported between white and Asian populations. [32][33][34] Enzyme polymorphisms have an impact on valproate serum concentrations. 35,36 This interethnic variability could explain differences in clearance between the development and validation data sets.…”

UGT1A1 genotype and irinotecan therapy: general review and implementation in routine practice

“…The most frequent TATA box variant in Caucasians is the UGT1A1*28 allele, with seven TA repeats leading to reduced transcription and enzyme activity (30% enzyme activity in *28 relative to *1 allele). Two other functional variants are located in the phenobarbital response enhancer module (PBREM), UGT1A1*60 (in linkage disequilibrium with TATA box variants), and UGT1A1*93; both are found homozygous in around 10% of Caucasians [19][20][21]. UGT1A1*28 allelic frequency is lower in Asian populations, with <3% of homozygous individuals [18].…”

“…UGT1A1*28 allelic frequency is lower in Asian populations, with <3% of homozygous individuals [18]. Two other functional variants are located in the phenobarbital response enhancer module (PBREM), UGT1A1*60 (in linkage disequilibrium with TATA box variants), and UGT1A1*93; both are found homozygous in around 10% of Caucasians [19][20][21]. The most fre-quent variants carried by Asian populations (not found in Caucasians) are single nucleotide polymorphisms (SNP) located in exon 1, namely UGT1A1*6 associated with a markedly reduced enzyme activity (~30% enzyme activity in homozygous patients) and UGT1A1*27 with almost completely abolished activity [22,23].…”

Role of pharmacogenetics of drug-metabolizing enzymes in treating osteosarcoma

“…Most extensive genetic variation exists in UGT1A and UGT2B genes [71,72], which have recently been confirmed by sequencing of UGT1A1, UGT2B7 and UGT2B15 in five different ethnic groups [73]. In general, polymorphisms and expression of UGTs have mainly been studied in normal tissues or in vitro experimental models because of their prevalent expression in liver and intestine.…”