Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences.
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.
Maekawa
Keiko
K
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.
Saeki
Mayumi
M
Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.
Saito
Yoshiro
Y
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.
Ozawa
Shogo
S
Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.|Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan.
Kurose
Kouichi
K
Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.|Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
Kaniwa
Nahoko
N
Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.|Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
Kawamoto
Manabu
M
Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
Kamatani
Naoyuki
N
Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
Kato
Ken
K
Gastrointestinal Oncology Division, National Cancer Center Hospital, National Cancer Center, Tokyo, Japan.
Hamaguchi
Tetsuya
T
Gastrointestinal Oncology Division, National Cancer Center Hospital, National Cancer Center, Tokyo, Japan.
Yamada
Yasuhide
Y
Gastrointestinal Oncology Division, National Cancer Center Hospital, National Cancer Center, Tokyo, Japan.
Shirao
Kuniaki
K
Gastrointestinal Oncology Division, National Cancer Center Hospital, National Cancer Center, Tokyo, Japan.
Shimada
Yasuhiro
Y
Gastrointestinal Oncology Division, National Cancer Center Hospital, National Cancer Center, Tokyo, Japan.
Muto
Manabu
M
Gastrointestinal Oncology Division, National Cancer Center Hospital East, Kashiwa, Japan.
Doi
Toshihiko
T
Division of GI Oncology/Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa, Japan.
Ohtsu
Atsushi
A
Division of GI Oncology/Digestive Endoscopy, National Cancer Center Hospital East, Kashiwa, Japan.
Yoshida
Teruhiko
T
Genetics Division, National Cancer Center Research Institute, National Cancer Center, Tokyo, Japan.
Matsumura
Yasuhiro
Y
Research Center of Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
Saijo
Nagahiro
N
Deputy Director, National Cancer Center Hospital East, Kashiwa, Japan.
Sawada
Jun-Ichi
JI
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.
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