title: Fourteen novel genetic variations and haplotype structures of the TYMS gene encoding human thymidylate synthase (TS).
abstract: Forty genetic variations including 14 novel ones were found in the human TYMS gene, which encodes thymidylate synthase, in 263 Japanese cancer patients who received 5-fluorouracil (FU)-based chemotherapy. Three novel variations were located within the 28-bp tandem repeat sequence in the 5'-untranslated region (UTR) and were designated 5Rc, 3Rc-ins and 4Rc. Allele frequencies were 0.021 for 5Rc, 0.006 for 3Rc-ins and 0.002 for 4Rc. Other novel variations included -133G>C and -125G>C in the 5'-UTR; IVS1-278G>A, IVS2-68C>T, IVS2-23T>C, IVS4+122_+123insATTG, IVS4-141G>A, IVS5-100A>T and IVS6-111G>A in the introns; and 1244(*302)A>G and 1264(*322)G>A in the 3'-UTR. The allele frequencies were 0.34 for IVS4+122_+123insATTG, 0.042 for -133G>C, 0.011 for IVS4-141G>A, 0.006 for -125G>C, 0.004 for IVS1-278G>A, IVS2-68C>T, 1244(*302)A>G and 1264(*322)G>A, and 0.002 for IVS2-23T>C, IVS5-100A>T and IVS6-111G>A. Using the detected polymorphisms, linkage disequilibrium (LD) analysis was performed, which divided the TYMS gene into three LD blocks. The 28-bp tandem repeat sequence in the 5'-UTR was assigned as Block 2 with a total of 7 alleles. In Blocks 1 and 3, 7 and 19 haplotypes were determined/inferred, respectively. Our findings provide fundamental and useful information for genotyping TYMS in the Japanese and probably other Asian populations.
authors.affiliation: Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan. kim@nihs.go.jp
authors.forename: Su-Ryang
authors.initials: SR
authors.lastname: Kim
authors.forename: Shogo
authors.initials: S
authors.lastname: Ozawa
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Kouichi
authors.initials: K
authors.lastname: Kurose
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kaniwa
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.forename: Manabu
authors.initials: M
authors.lastname: Muto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005472:Fluorouracil / Q000627:therapeutic use; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007438:Introns; D007564:Japan; D015810:Linkage Disequilibrium; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D020080:Tandem Repeat Sequences; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D013940:Thymidylate Synthase; D005472:Fluorouracil