Genetic variations and haplotype structures of transcriptional factor Nrf2 and its cytosolic reservoir protein Keap1 in Japanese

被引:17
作者
Fukushima-Uesaka, Hiromi
Saito, Yoshiro
Maekawa, Keiko
Kamatani, Naoyuki
Kajio, Hiroshi
Kuzuya, Nobuaki
Noda, Mitsuhiko
Yasuda, Kazuki
Sawada, Jun-ichi
机构
[1] Natl Inst Hlth Sci, Div Biochem & Immunochem, Setagaya Ku, Tokyo 1588501, Japan
[2] Natl Inst Hlth Sci, Project Team Pharmacogenet, Tokyo 158, Japan
[3] Tokyo Womens Med Univ, Div Genom Med, Dept Adv Biomed Engn & Sci, Tokyo, Japan
[4] Int Med Ctr Japan, Div Endocrinol & Metab Dis, Hosp, Tokyo, Japan
[5] Int Med Ctr, Dept Metab Disorder, Res Inst, Tokyo, Japan
关键词
NFE2L2; KEAP1; novel genetic variation; amino acid change; haplotype;
D O I
10.2133/dmpk.22.212
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Transcriptional factor Nrf2 and its cystosolic reservoir protein Keap1 play important roles in induction of the expression of genes for xenobiotic metabolism and disposition, many of which are involved in protection from oxidative stress. In this study, 5 NFE2L2 (encoding Nrf2) and 6 KEAP1 exons and their flanking introns were comprehensively screened for genetic variations in 84 Japanese subjects. As for NFE2L2, 14 genetic variations were found, including 9 novel ones: 7 were located in the 5'-flanking region, 1 in the 5'-untranslated region (5'-UTR), 3 (1 synonymous and 2 nonsynonymous) in the coding exons, 1 in the intron, and 2 in the 3'-UTR. Two novel nonsynonymous variations, 697C>T (Pro233Ser) and 1094G>T (Ser365Ile), were heterozygously found with allele frequencies of 0.012 and 0.006, respectively. Regarding KEAP1, 18 genetic variations were detected, including 13 novel ones: 2 were located in the 5'-flanking region, 4 in the coding exons (4 synonymous), 5 in the introns, 4 in the 3'-UTR, and 3 in the 3'-flanking region. Based on the linkage disequilibrium (LD) profiles, both genes were analyzed as single LD blocks, where 14 (NFE2L2) and 18 (KEAP1) haplotypes were inferred. Six (NFE2L2) and 5 (KEAP1) haplotypes were relatively prevalent (>= 0.03 frequencies) and accounted for >= 88% of the inferred haplotypes. These data would be fundamental and useful information for pharmacogenetic studies on Nrf2-regulated genes for xenobiotic metabolism and disposition.
引用
收藏
页码:212 / 219
页数:8
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