Genetic Variations and Haplotype Structures of Transcriptional Pactor Nrf2 and Its Cytosolic Reservoir Protein Keap1 in Japanese

Summary:Transcriptional factor Nrf2 and its cytosolic reservoir protein KeapI play important rôles 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 NPE2L2 (encoding Nrf2) and 6 KEAPI exons and their flanking introns were comprehensively screened for genetic variations in 84 Japanese subjects. As for NPE2L2, 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 KEAPI, 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 (NPE2L2) and 18 (KEAPI ) haplotypes were inferred. Six (NPE2L2) and 5 (KEAPI ) haplotypes were relatively prevalent (≥ 0.03 frequencies) and accounted for ≥ 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 phar- macogenetic studies on Nrf2-regulated genes for xenobiotic metabolism and disposition.