title: Genetic variations and haplotype structures of the ABC transporter gene ABCC1 in a Japanese population.
abstract: Multidrug resistance-related protein 1 (MRP1), an ATP-binding cassette transporter encoded by the ABCC1 gene, is expressed in many tissues, and functions as an efflux transporter for glutathione-, glucuronate- and sulfate-conjugates as well as unconjugated substrates. In this study, the 31 exons and their flanking introns of ABCC1 were comprehensively screened for genetic variations in 153 Japanese subjects to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCC1 that is necessary for pharmacogenetic studies of the substrate drugs. Eighty-six genetic variations including 31 novel ones were found: 1 in the 5'-flanking region, 1 in the 5'-untranslated region (UTR), 20 in the coding exons (9 synonymous and 11 nonsynonymous variations), 4 in the 3'-UTR, and 60 in the introns. Of these, eight novel nonsynonymous variations, 726G>T (Trp242Cys), 1199T>C (Ile400Thr), 1967G>C (Ser656Thr), 2530G>A (Gly844Ser), 3490G>A (Val1164Ile), 3550G>A (Glu1184Lys), 3901C>T (Arg1301Cys), and 4502A>G (Asp1501Gly), were detected with an allele frequency of 0.003. Based on the LD profiles, the analyzed regions of the gene were divided into five LD blocks (Blocks -1 and 1 to 4). The multiallelic repeat polymorphism in the 5'-UTR was defined as Block -1. For Blocks 1, 2, 3 and 4, 32, 23, 23 and 13 haplotypes were inferred, and 9, 7, 7 and 6 haplotypes commonly found on > or = 10 chromosomes accounted for > or = 91% of the inferred haplotypes in each block. Haplotype-tagging single nucleotide polymorphisms for each block were identified to capture the common haplotypes. This study would provide fundamental and useful information for the pharmacogenetic studies of MRP1-dependently effluxed drugs in Japanese.
authors.affiliation: Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fukushima-Uesaka
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tohkin
authors.forename: Keiko
authors.initials: K
authors.lastname: Maekawa
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Hasegawa
authors.forename: Manabu
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Kazuko
authors.initials: K
authors.lastname: Suzuki
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Yanagawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kajio
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Kuzuya
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yasuda
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics; D004247:DNA / Q000235:genetics; D003920:Diabetes Mellitus / Q000235:genetics; D005091:Exons / Q000235:genetics; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics; D007564:Japan; D015810:Linkage Disequilibrium / Q000235:genetics; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D004247:DNA; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1