Association study between single-nucleotide polymorphisms in 199 drug-related genes and commonly measured quantitative traits of 752 healthy Japanese subjects

Abstract

With dense single-nucleotide polymorphism (SNP) maps for 199 drug-related genes, we examined associations between 4190 SNPs and 38 commonly measured quantitative traits using data from 752 healthy Japanese subjects. On analysis, we observed a strong association between five SNPs within the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene and serum total bilirubin levels (minimum P-value in Mann-Whitney test¼1.82Â10 10 ). UGT1A1 catalyzes the conjugation of bilirubin with glucuronic acid, thus enhancing bilirubin elimination. This enzyme is known to play an important role in the variation of serum bilirubin levels. The five SNPs, including a nonsynonymous SNP-rs4148323 (211G4A or G71R variant allele known as UGT1A1*6)-showed strong linkage disequilibrium with each other. No other genes were clearly associated with serum total bilirubin levels. Results of linear multiple regression analysis on serum total bilirubin levels followed by analysis of variance showed that at least 13% of the variance in serum total bilirubin levels could be explained by three haplotype-tagging SNPs in the UGT1A1 gene.

Exome-Wide Association Study Identifies New Low-Frequency and Rare UGT1A1 Coding Variants and UGT1A6 Coding Variants Influencing Serum Bilirubin in Elderly Subjects

“…The independent replication study was performed on 227 Italian subjects from the Gagliano Castelferrato commune (Sicily, Enna). As the 3 intronic variants of UGT1A1 have been previously reported and validated for their association with serum bilirubin level, 22 – 29 we report here replication data on the 3 exonic missense variants on UGT1A6 (rs6759892, p.Ser7Ala; rs2070959, p.Thr181Ala; and rs1105879, p.Arg184Ser). These variants were significantly associated with total serum bilirubin level, as well as unconjugated and conjugated serum bilirubin levels (Table 2 ).…”

“…Several SNPs in the UGT1A1 locus have been reported in previous studies to be significantly associated with serum bilirubin. 22 – 29 , 32 – 34 The reported UGT1A1 SNPs are intronic (rs6742078, rs887829, rs4148324, and rs4148325) and are in complete linkage disequilibrium within the same haplotype block. 24 To date, outside of published polymorphisms on UGT1A1 gene isoform, no data have been reported regarding potential variants on other isoforms of UGT1A gene complex in physiological conditions.…”

“…Among the 4 low-frequency and rare variants that we found on the exon-1 of the UGT1A1 gene, only 1 (rs4148323, p.Gly71Arg) has been reported to be associated with serum bilirubin level in Asian populations. 22 , 29 , 33 , 35 , 36 Using the 1000 genomes database, the MAF of the rs4148323 (p.Gly71Arg) variant was 0.9% in Europeans versus 17.3% in East Asians. Regarding the 3 other missense variants that we found on UGT1A1 first exon, the MAFs in Europeans for rs144398951 (p.Ile215Val), rs35003977 (p.Val225Gly), and rs57307513 (p.Ser250Pro) were 0% (Exome Sequencing Project, ESP6500), 0.1% (ESP6500), and 0% (1000 genomes), respectively.…”

Prevalence of topoisomerase I genetic mutations and UGT1A1 polymorphisms associated with irinotecan in individuals of Asian descent

“…Genetic polymorphisms of the UGT1A1 gene were revealed to explain the variability of CPT-11-related toxicity among patients, particularly UGT1A1*28 [(TA) 7 TAA], the existence of which is known to be predictive of CPT-11-induced neutropenia (11). In addition, the UGT1A1*6 and *27 alleles, two variants in exon 1 of the UGT1A1 gene, are found mainly among individuals of Asian descent, and have also been indicated to affect enzyme function (12,13 exon: UGT1A1*6) within the UGT1A1 gene and serum total bilirubin levels was noted in Japanese subjects (15). Although the TOP-I mutation-related CPT-11 resistance has been elucidated, the prevalence of TOP-I germline mutation has yet to be investigated.…”

A novel rare copy number variant of the ABCF1 gene identified among dengue fever patients from Peninsular Malaysia

“…This gene family transports a wide range of substrate molecules across intra-and extra-cellular membranes (Dean and Allilmets, 2001) and serves as an important component of cellular defense mechanisms. Many of these genes have been attributed to a number of autoimmune and inflammatory diseases (Dean and Allilmets, 2001;Ota et al, 2007;Paladini et al, 2009); drug resistance (Saito et al, 2009); and a variety of diseases with complex or Mendelian genetics (Gillet et al, 2007). The ATP-binding cassette subfamily F member 1 (ABCF1) gene is a member of the GCN20 subfamily, located at 6p21.33 adjacent to HLA-E in the MHC region (Paladini et al, 2009), with a size of ~21 kb ( Figure 1).…”