title: Genetic variations and haplotypes of UGT1A4 in a Japanese population.
abstract: Nineteen genetic variations, including 11 novel ones, were found in exon 1 and its flanking region of the UDP-glucuronosyltransferase (UGT) 1A4 gene from 256 Japanese subjects, consisting of 60 healthy volunteers, 88 cancer patients and 108 arrhythmic patients. These variations include -217T>G and -36G>A in the 5'-flanking region, 30G>A (P10P), 127delA (43fsX22; frame-shift from codon 43 resulting in the termination at the 22nd codon, codon 65), 175delG (59fsX6), 271C>T (R91C), 325A>G (R109G), and 357T>C (N119N) in exon 1, and IVS1+1G>T, IVS1+98A>G and IVS1+101G>T in the following intron. Among them, 127delA and 175delG can confer early termination of translation, resulting in an immature protein that probably lacks enzymatic activity. Variation IVS1+1G>T is located at a splice donor site and thus may lead to aberrant splicing. Since we did not find any significant differences in the frequencies of all the variations among the three subject groups, the data were analyzed as one group. The allele frequencies of the novel variations were 0.006 for IVS1+101G>T, 0.004 for 30G>A (P10P) and 357T>C (N119N), and 0.002 for the 8 other variations. In addition, the two known nonsynonymous single nucleotide polymorphisms (SNPs), 31C>T (R11W) and 142T>G (L48V), were found at 0.012 and 0.129 frequencies, respectively. The SNP 70C>A (P24T), mostly linked with 142T>G (L48V) in German Caucasians, was not detected in this study. Sixteen haplotypes were identified or inferred, and some haplotypes were confirmed by cloning and sequencing. It was shown that most of 142T>G (L48V) was linked with -219C>T, -163G>A, 448T>C (L150L), 804G>A (P268P), and IVS1+43C>T, comprising haplotype *3a; haplotype *4a harbors 31C>T (R11W); 127delA (43fsX22) and 142T>G (L48V) were linked (haplotype *5a); 175delG (59fsX6) was linked with 325A>G (R109G) (*6a haplotype); and -219C>T, -163G>A, 142T>G (L48V), 271C>T (R91C), 448T>C (L150L), 804G>A (P268P), and IVS1+43C>T comprised haplotype *7a. Our results provide fundamental and useful information for genotyping UGT1A4 in the Japanese and probably Asian populations.
authors.affiliation: Project Team for Pharmacogenetics, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Saeki
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Hideto
authors.initials: H
authors.lastname: Jinno
authors.forename: Kimie
authors.initials: K
authors.lastname: Sai
authors.forename: Akiko
authors.initials: A
authors.lastname: Hachisuka
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kaniwa
authors.forename: Shogo
authors.initials: S
authors.lastname: Ozawa
authors.forename: Manabu
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Kazuo
authors.initials: K
authors.lastname: Komamura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kotake
authors.forename: Hideki
authors.initials: H
authors.lastname: Morishita
authors.forename: Shiro
authors.initials: S
authors.lastname: Kamakura
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.forename: Hitonobu
authors.initials: H
authors.lastname: Tomoike
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
mesh_terms: D001145:Arrhythmias, Cardiac / Q000201:enzymology; D044466:Asian People; D014644:Genetic Variation; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D009369:Neoplasms / Q000201:enzymology; D011110:Polymorphism, Genetic
chemical_list: C019787:bilirubin glucuronoside glucuronosyltransferase; D014453:Glucuronosyltransferase