title: Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences.
abstract: Dihydropyrimidine dehydrogenase (DPD) is an inactivating and rate-limiting enzyme for 5-fluorouracil (5-FU), and its deficiency is associated with a risk for developing a severe or fatal toxicity to 5-FU. In this study, to search for genetic variations of DPYD encoding DPD in Japanese, the putative promoter region, all exons, and flanking introns of DPYD were sequenced from 341 subjects including cancer patients treated with 5-FU. Fifty-five genetic variations, including 38 novel ones, were found and consisted of 4 in the 5'-flanking region, 21 (5 synonymous and 16 nonsynonymous) in the coding exons, and 30 in the introns. Nine novel nonsynonymous SNPs, 29C>A (Ala10Glu), 325T>A (Tyr109Asn), 451A>G (Asn151Asp), 733A>T (Ile245Phe), 793G>A (Glu265Lys), 1543G>A (Val515Ile), 1572T>G (Phe524Leu), 1666A>C (Ser556Arg), and 2678A>G (Asn893Ser), were found at allele frequencies between 0.15 and 0.88%. Two known nonsynonymous variations reported only in Japanese, 1003G>T (*11, Val335Leu) and 2303C>A (Thr768Lys), were found at allele frequencies of 0.15 and 2.8%, respectively. SNP and haplotype distributions in Japanese were quite different from those reported previously in Caucasians. This study provides fundamental information for pharmacogenetic studies for evaluating the efficacy and toxicity of 5-FU in Japanese and probably East Asians.
authors.affiliation: Division of Biochemistry and Immunochemistry, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan. maekawa@nihs.go.jp.|Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan. maekawa@nihs.go.jp.
authors.forename: Keiko
authors.initials: K
authors.lastname: Maekawa
authors.affiliation: Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Saeki
authors.affiliation: Division of Biochemistry and Immunochemistry, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.|Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.|Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Ozawa
authors.affiliation: Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.|Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Kurose
authors.affiliation: Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.|Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kaniwa
authors.affiliation: Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Kawamoto
authors.affiliation: Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, National Cancer Center, Tokyo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Kato
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, National Cancer Center, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, National Cancer Center, Tokyo, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, National Cancer Center, Tokyo, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, National Cancer Center, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Muto
authors.affiliation: Division of GI Oncology/Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.affiliation: Division of GI Oncology/Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.affiliation: Genetics Division, National Cancer Center Research Institute, National Cancer Center, Tokyo, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Research Center of Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
authors.affiliation: Deputy Director, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.affiliation: Division of Biochemistry and Immunochemistry, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan.|Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Sawada
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D044466:Asian People / Q000208:ethnology / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000633:toxicity*; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007564:Japan / Q000208:ethnology; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide