title: Genetic variations and haplotype structures of transcriptional factor Nrf2 and its cytosolic reservoir protein Keap1 in Japanese.
abstract: Transcriptional factor Nrf2 and its cytosolic 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 (>or=0.03 frequencies) and accounted for >or=88% of the inferred haplotypes. Haplotype-tagging variations of each gene were identified to capture these prevalent haplotypes. These data would be fundamental and useful information for pharmacogenetic studies on Nrf2-regulated genes for xenobiotic metabolism and disposition.
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: Keiko
authors.initials: K
authors.lastname: Maekawa
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kajio
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Kuzuya
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Noda
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yasuda
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
mesh_terms: D024509:3' Flanking Region; D024506:5' Flanking Region; D000368:Aged; D019943:Amino Acid Substitution; D044466:Asian People / Q000235:genetics*; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007564:Japan; D000072019:Kelch-Like ECH-Associated Protein 1; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human