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Catalog of 680 Variations Among Eight Cytochrome P450 (CYP) Genes

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Catalog of 680 Variations Among Eight Cytochrome P450 (CYP) Genes J Hum Genet (2003) 48:249–270 DOI 10.1007/s10038-003-0021-7 ORIGINAL ARTICLE Susumu Saito Æ Aritoshi Iida Æ Akihiro Sekine Saori Kawauchi Æ Shoko Higuchi Æ Chie Ogawa Yusuke Nakamura Catalog of 680 variations among eight cytochrome P450 (CYP ) genes, nine esterase genes, and two other genes in the Japanese population Received: 4 March 2003 / Accepted: 6 March 2003 / Published online: 29 April 2003 Ó The Japan Society of Human Genetics and Springer-Verlag 2003 Abstract We screened DNAs from 48 Japanese indi- are classified into families and subfamilies on the basis of viduals for single-nucleotide polymorphisms (SNPs) in sequence similarities, and among them, numerous eight cytochrome P450 (CYP) genes, nine esterase polymorphisms have been previously reported [Human genes, and two other genes by directly sequencing the Cytochrome P450 (CYP) Allele Nomenclature Com- relevant genomic regions in their entirety except for mittee, http://www.imm.ki.se/CYPalleles/]. The prod- repetitive elements. This approach identified 607 SNPs ucts of these and the other eleven genes selected for the and 73 insertion/deletion polymorphisms among the 19 work reported here are described in the following genes examined. Of the 607 SNPs, 284 were identified paragraphs. in CYP genes, 302 in esterase genes, and 21 in the other CYP2A6 is a major player in the oxidation of nico- two genes (GGT1, and TGM1); overall, 37 SNPs were tine and coumarin in human liver microsomes (Nakaj- located in 5’ flanking regions, 496 in introns, 55 in ima et al. 1996a; 1996b). Polymorphisms of CYP2A6 exons, and 19 in 3’ flanking regions. These variants that might affect enzymatic activity (Ariyoshi et al. 2001; should contribute to studies designed to investigate Kitagawa et al. 2001; Pitarque et al. 2001; Daigo et al. possible correlations between genotypes and pheno- 2002; Oscarson et al. 2002; Xu et al. 2002) or suscepti- types of disease susceptibility or responsiveness to drug bility to lung cancer (Pianezza et al. 1998; London et al. therapy. 1999; Miyamoto et al. 1999) have been reported. How- ever, some of those variants may be rare substitutions or Keywords Single-nucleotide polymorphism (SNP) Æ limited to specific ethnic groups (Kitagawa et al. 2001; Cytochrome P450 (CYP) Æ Esterase Æ GGT1 Æ TGM1 Oscarson et al. 1999, 2002; Xu et al. 2002). CYP2A13 may play important roles in xenobiotic toxicity and tobacco-related tumorigenesis in the respi- ratory tract (Su et al. 2000). Zhang et al. (2002) have Introduction identified a C-to-T polymorphism (Arg257Cys) in exon 5 of the gene, and the product of this variant Cytochrome P450 (CYP) enzymes, many of which can is 37% to 56% less active than the wild-type protein catalyze xenobiotic compounds, constitute a superfamily toward all substrates tested. of hemoproteins (Ding and Kaminsky 2003). CYP genes CYP2B6 is involved in the metabolism of several clinically important drugs (Ekins and Wrighton 1999). Lang et al. (2001) have identified five polymorphisms that would affect amino acid sequences; among them, a S. Saito Æ A. Iida Æ A. Sekine Æ S. Kawauchi Æ S. Higuchi C-to-T polymorphism (Arg487Cys) in exon 9 of the Y. Nakamura Laboratory for Genotyping, SNP Research Center, gene appears to be associated with enzymatic activity. Institute of Physical and Chemical Research, However, some of those five variants could also be Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, rare substitutions or limited to specific ethnic groups Yokohama 230-0045, Japan (Hiratsuka et al. 2002). C. Ogawa Æ Y. Nakamura (&) CYP2E catalyzes the conversion of ethanol to acet- Laboratory of Molecular Medicine, Human Genome Center, aldehyde and to acetate and also metabolizes the pre- Institute of Medical Science, University of Tokyo, mutagenic nitrosamines present in cigarette smoke 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan E-mail: [email protected] (Guengerich et al. 1991). Polymorphisms have been Tel.: +81-3-54495372 associated with increased risk of alcohol-related liver Fax: +81-3-54495433 disease (Tanaka et al. 1997; Sun et al. 1999), lung cancer 250 Table 1 Accession numbers for the genomic and cDNA sequences used in this study Gene name Chromosomal Accession no. localization Genomic sequence cDNA sequence CYP CYP2A6 19q13.2 NG_000008.2 NM_000762.3 CYP2A13 19q13.2 AC008962.9 NM_000766.2 CYP2B6 19q13.2 NG_000010.1 NM_000767.3 CYP2E 10q24.3-qter AL161645.14 NM_000773.2 CYP2S1 19q13.1 NG_000011.1 NM_030622.2 TBXAS1 7q34-q35 AC006021.2 AC004914.1 AC004961.2 XM_034816.1 CYP7A1 8q11-q12 AC020782.10 XM_044651.1 CYP7B1 8q21.3 AF127089.1 AF215845.2 AF176800.1 NM_004820.2 Esterase AADAC 3q21.3-q25.2 AC068647.4 L32179.1 CEL 9q34.3 AL138750.8 AL162417.20 AF072711.1 NM_001807.1 CES1 16q13-q22.1 AC007602.4 L07764.1 CES2 16q21 AC027131.4 XM_043817.1 ESD 13q14.1-q14.2 AL136958.9 AF112219.1 GZMA 5q11-q12 AC091977.1 NM_006144.2 GZMB 14q11.2 AL136018.3 XM_12328.3 XM_032600.1 M38193.1 IL17 6p12 AL355513.11 U32659.1 UCHL3 13q21.33 AL137244.28 NM_006002.1 Other genes GGT1 22q11.23 D87002.1 L20490.1 TGM1 14q11.2 M98447.1 M55183.1 Table 2 Summary of genetic variations in 19 genes (SNP Gene All genetic SNPs Insertion/ Novel Total Frequency single-nucleotide variations deletion base pairs (bp/1 SNP) polymorphism) polymorphisms sequenced (kb) CYP CYP2A6 22 22 0 13 4.8 218 CYP2A13 15 15 0 11 6.7 447 CYP2B6 24 24 0 14 7.0 292 CYP2E 42 40 2 18 11.9 298 CYP2S1 19 14 5 9 6.5 464 TBXAS1 158 137 21 87 86.5 631 CYP7A1 18 16 2 13 9.0 563 CYP7B1 21 16 5 18 21.3 1331 Total (CYP) 319 284 35 183 153.7 (average) 541 Esterase AADAC 24 23 1 7 12.1 526 CEL 132 117 15 84 54.8 468 CES1 52 47 5 34 19.2 409 CES2 9 6 3 6 8.1 1350 ESD 29 28 1 14 22.3 796 GZMA 9 9 0 2 8.1 900 GZMB 14 13 1 10 6.4 492 IL17 11 11 0 6 7.8 709 UCHL3 60 48 12 47 32.8 683 Total (Esterase) 340 302 38 210 171.6 (average) 568 Others GGT1 7 7 0 7 2.6 371 TGM1 14 14 0 5 13.7 979 Total (Others) 21 21 0 12 16.3 (average) 776 Total (All) 680 607 73 405 341.6 563 (el-Zein et al. 1997; Oyama et al. 1997; Wu et al. 1997), enzyme that is expressed mainly in trachea, lung, nasopharyngeal carcinoma (Hildesheim et al. 1997), and stomach, small intestine, and spleen. Rivera et al. (2002) oral cancer (Hung et al. 1997). have reported that CYP2S1 is inducible by 2,3,7,8-tet- By screening a database of expressed-sequence tags, rachlorodibenzo-p-dioxin (dioxin) in a cell line derived Rylander et al. (2001) have identified CYP2S1, a P450 from human lung epithelium. 251 Fig. 1a–h Locations of single-nucleotide polymorphisms (SNPs) in CYP7A1 encodes cholesterol 7-alpha-hydroxylase, the CYP2A6 (a), CYP2A13 (b), CYP2B6 (c), CYP2E (d), CYP2S1 the rate-limiting enzyme for the conversion of choles- (e), TBXAS1 (f), CYP7A1 (g), and CYP7B1 (h) genes (vertical lines). Open boxes Exons, hatching unsequenced regions of terol to bile acids in the liver (Jelinek et al. 1990). The repetitive elements, ATG initiation codon, TGA, TAG stop codons promoter region of this gene contains a potential DNA- binding site for the transcription factor CPF; mutation Thromboxane A synthase (TBXAS1, CYP5A1) cat- of the CPF-binding site abolishes hepatic-specific alyzes the conversion of prostaglandin endoperoxide expression in transient transfection assays (Nitta et al. into thromboxane A2 (Shen and Tai 1986; Jones and 1999). Wang et al. (1998) have identified two linked Fitzpatrick 1991). TBXAS1 plays an important role in polymorphisms in the 5’flanking region of CYP7A1; the hemostasis and in cardiovascular diseases (FitzGerald allele defined by these polymorphisms is associated with et al. 1990). Although eleven polymorphisms have been increased concentrations of low-density lipoprotein identified in the promoter region, coding sequences, or cholesterol in plasma. 3’-untranslated region (3’UTR) of the TBXAS1 gene, CYP7B1 encodes oxysterol 7-alpha-hydroxylase the biological effects of these variants are currently un- (Setchell et al. 1998). This enzyme not only participates known (Chevalier et al. 2001). the synthesis of primary bile acids from cholesterol but 252 Fig. 1a–h (Continued) 253 Table 3 Summary of genetic a variations detected in the Gene and Location Position Genetic NCBI SNP ID CYP2A6 gene, CYP2A13 gene, variation no. variation CYP2B6 gene, CYP2E gene, CYP2S1 gene, TBXAS1 gene, CYP2A6 CYP7A1 gene, and CYP7B1 1 Exon 1 31 C/T (Leu8Leu) gene (CYP2A6 Cytochrome 2 Exon 1 60 G/A (Val17Val) rs1137115 P450, subfamily IIA, 3 Exon 1 153 G/A (Gln48Gln) polypeptide 6, CYP2A13 4 Intron 1 29 C/T Cytochrome P450, subfamily 5 Intron 1 98 G/A IIA, polypeptide 13, CYP2B6 6 Intron 1 153 C/T Cytochrome P450, subfamily 7 Intron 2 1011 C/T IIB, polypeptide 6, CYP2E 8 Intron 3 23 G/T Cytochrome P450, subfamily 9 Intron 3 77 G/C IIE, CYP2S1 Cytochrome 10 Intron 4 275 A/G rs2388868 P450, subfamily IIS, 11 Exon 5 117 C/T (Arg257Arg) rs1809811 polypeptide 1, TBXAS1 12 Intron 6 323 C/A Thromboxane A synthase 1, 13 Intron 7 203 G/A CYP7A1 Cytochrome P450, 14 Intron 7 440 A/C rs2316210 subfamily VIIA, polypeptide 1, 15 Exon 8 84 C/T (His415His) rs2002977 CYP7B1 Cytochrome P450, 16 Exon 8 96 G/C (Glu419Asp) subfamily VIIB, polypeptide 1, 17 Intron 8 27 C/T rs2002976 NCBI National Center for 18 Intron 8 47 G/C rs2002975 b Biotechnology Information, 19 Exon 9 109 T/C (Ile471Thr) UTR untranslated region, 20 Exon 9 333 C/G (3’UTR) rs696839 del deletion, ins insertion) 21 Exon 9 383 A/G (3’UTR) 22 Exon 9 386 C/A (3’UTR) CYP2A13 1 5’ Flanking )402 G/A rs305987 2 5’ Flanking )251 C/T 3 5’ Flanking )112 T/C 4 Exon 1 83 G/A (Arg25Gln) 5 Exon 2 121 C/T (Arg101Stop) 6 Intron 4 118 T/C 7 Intron
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