Haplotypes ofCYP3A4 and their close linkage withCYP3A5 haplotypes in a Japanese population

作者：Hiromi Fukushima‐Uesaka, Yoshiro Saito, Hidemi Watanabe, Kisho Shiseki, Mayumi Saeki, Takahiro Nakamura, Kouichi Kurose, Kimie Sai, Kazuo Komamura, Kazuyuki Ueno, Shiro Kamakura, Masafumi Kitakaze, Sotaro Hanai, Toshiharu Nakajima, Kenji Matsumoto, Hirohisa Saito, Yu‐ichi Goto, Hideo Kimura, Masaaki Katoh, Kenji Sugai, Narihiro Minami, Kuniaki Shirao, Tomohide Tamura, Noboru Yamamoto, Hironobu Minami, Atsushi Ohtsu, Teruhiko Yoshida, Nagahiro Saijo, Yutaka Kitamura, Naoyuki Kamatani, Shogo Ozawa, Jun‐ichi Sawada · 发表于：Human Mutation · 年份：2003 · DOI：10.1002/humu.9210 · 被引用次数：165 · 研究领域：Eicosanoids and Hypertension Pharmacology、Pharmacogenetics and Drug Metabolism、Cancer, Hypoxia, and Metabolism

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 pro...