title: Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population.
abstract: In order to identify single nucleotide polymorphisms (SNPs) and haplotype frequencies of CYP3A4 in a Japanese population, the distal enhancer and proximal promoter regions, all exons, and the surrounding introns were sequenced from genomic DNA of 416 Japanese subjects. We found 24 SNPs, including 17 novel ones: two in the distal enhancer, four in the proximal promoter, one in the 5'-untranslated region (UTR), seven in the introns, and three in the 3'-UTR. The most common SNP was c.1026+12G>A (IVS10+12G>A), with a 0.249 frequency. Four non-synonymous SNPs, c.554C>G (p.T185S, CYP3A4(*)16), c.830_831insA (p.E277fsX8, (*)6), c.878T>C (p.L293P, (*)18), and c.1088 C>T (p.T363M, (*)11) were found with frequencies of 0.014, 0.001, 0.028, and 0.002, respectively. No SNP was found in the known nuclear transcriptional factor-binding sites in the enhancer and promoter regions. Using these 24 SNPs, 16 haplotypes were unambiguously identified, and nine haplotypes were inferred by aid of an expectation-maximization-based program. In addition, using data from 186 subjects enabled a close linkage to be found between CYP3A4 and CYP3A5 SNPs, especially among the SNPs at c.1026+12 in CYP3A4 and c.219-237 (IVS3-237, a key SNP site for CYP3A5(*)3), c.865+77 (IVS9+77) and c.1523 in CYP3A5. This result suggested that CYP3A4 and CYP3A5 are within the same gene block. Haplotype analysis between CYP3A4 and CYP3A5 revealed several major haplotype combinations in the CYP3A4-CYP3A5 block. Our findings provide fundamental and useful information for genotyping CYP3A4 (and CYP3A5) in the Japanese, and probably Asian populations.
authors.affiliation: Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fukushima-Uesaka
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Hidemi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Kisho
authors.initials: K
authors.lastname: Shiseki
authors.forename: Mayumi
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authors.lastname: Saeki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Kouichi
authors.initials: K
authors.lastname: Kurose
authors.forename: Kimie
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authors.lastname: Sai
authors.forename: Kazuo
authors.initials: K
authors.lastname: Komamura
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Ueno
authors.forename: Shiro
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authors.lastname: Kamakura
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.forename: Sotaro
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authors.lastname: Hanai
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Nakajima
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.forename: Yu-ichi
authors.initials: Y
authors.lastname: Goto
authors.forename: Hideo
authors.initials: H
authors.lastname: Kimura
authors.forename: Masaaki
authors.initials: M
authors.lastname: Katoh
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugai
authors.forename: Narihiro
authors.initials: N
authors.lastname: Minami
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
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: Yutaka
authors.initials: Y
authors.lastname: Kitamura
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: D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005787:Gene Frequency; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D007564:Japan; D020641:Polymorphism, Single Nucleotide
chemical_list: D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human