title: Genetic variation and haplotype structure of the ABC transporter gene ABCG2 in a Japanese population.
abstract: The ATP-binding cassette transporter, ABCG2, which is expressed at high levels in the intestine and liver, functions as an efflux transporter for many drugs, including clinically used anticancer agents such as topotecan and the active metabolite of irinotecan (SN-38). In this study, to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCG2, we have comprehensively searched for genetic variations in the putative promoter region, all the exons, and their flanking introns of ABCG2 from 177 Japanese cancer patients treated with irinotecan. Forty-three genetic variations, including 11 novel ones, were found: 5 in the 5'-flanking region, 13 in the coding exons, and 25 in the introns. In addition to 9 previously reported nonsynonymous single nucleotide polymorphisms (SNPs), 2 novel nonsynonymous SNPs, 38C>T (Ser13Leu) and 1060G>A (Gly354Arg), were found with minor allele frequencies of 0.3%. Based on the LD profiles between the SNPs and the estimated past recombination events, the region analyzed was divided into three blocks (Block -1, 1, and 2), each of which spans at least 0.2 kb, 46 kb, and 13 kb and contains 2, 24, and 17 variations, respectively. The two, eight, and five common haplotypes detected in 10 or more patients accounted for most (>90%) of the haplotypes inferred in Block -1, Block 1, and Block 2, respectively. The SNP and haplotype distributions in Japanese were different from those reported previously in Caucasians. This study provides fundamental information for the pharmacogenetic studies investigating the relationship between the genetic variations in ABCG2 and pharmacokinetic/pharmacodynamic parameters.
authors.affiliation: Project Team for Pharmacogenetics, Division of Biochemistry and Immunochemistry, National Institute of Health Sciences, Kamiyoga, Tokyo, Japan. maekawa@nihs.go.jp
authors.forename: Keiko
authors.initials: K
authors.lastname: Maekawa
authors.forename: Masaya
authors.initials: M
authors.lastname: Itoda
authors.forename: Kimie
authors.initials: K
authors.lastname: Sai
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kaniwa
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.forename: Hideo
authors.initials: H
authors.lastname: Kunitoh
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kubota
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: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Shogo
authors.initials: S
authors.lastname: Ozawa
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D004247:DNA / Q000235:genetics; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D000077146:Irinotecan; D007564:Japan; D015810:Linkage Disequilibrium / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D000077146:Irinotecan; D004247:DNA; D002166:Camptothecin