title: Four novel defective alleles and comprehensive haplotype analysis of CYP2C9 in Japanese.
abstract: Genetic variations in cytochrome P450 2C9 (CYP2C9) are known to contribute to interindividual and interethnic variability in response to clinical drugs such as warfarin. In the present study, CYP2C9 from 263 Japanese subjects was resequenced, resulting in the discovery of 62 variations including 32 novel ones. In addition to the two known non-synonymous single nucleotide polymorphisms (SNPs), Ile359Leu (*3; allele frequency=0.030) and Leu90Pro (*13; 0.002), seven novel non-synonymous SNPs, Leu17Ile (0.002), Lys118ArgfsX9 (*25; 0.002), Thr130Arg (*26; 0.002), Arg150Leu (*27; 0.004), Gln214Leu (*28; 0.002), Pro279Thr (*29; 0.002) and Ala477Thr (*30; 0.002), were found. Functional characterization of novel alleles using a mammalian cell expression system in vitro revealed that *25 was a null allele and that *26, *28 and *30 were defective alleles. The *26 product showed a 90% decrease in the Vmax value but little change in the Km value towards diclofenac. Both *28 and *30 products showed two-fold higher Km values and three-fold lower Vmax values than the *1 allele, suggesting the importance of Gln214 and Ala477 for substrate recognition. Linkage disequilibrium and haplotype analyses were performed using the detected variations. Only five haplotypes (frequency >0.02) accounted for most (>87%) of the inferred haplotypes, and they were closely associated with the haplotypes of CYP2C19 in Japanese. Although the haplotype structure of CYP2C9 was rather simple in Japanese, the haplotype distribution was quite different from those previously reported in Caucasians and Africans. Taken together, novel defective alleles and detailed haplotype structures would be useful for determining metabolic phenotypes of CYP2C9 substrate drugs in Japanese and probably Asians.
authors.affiliation: Project Team for Pharmacogenetics, Division of Biochemistry and Immunochemistry, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. maekawa@nihs.go.jp
authors.forename: Keiko
authors.initials: K
authors.lastname: Maekawa
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fukushima-Uesaka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tohkin
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Hasegawa
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: 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: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
mesh_terms: D000483:Alleles; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D003920:Diabetes Mellitus; D004008:Diclofenac / Q000378:metabolism*; D040461:Gene Components; D015870:Gene Expression; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D006899:Mixed Function Oxygenases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19