Functional polymorphisms in Nrf2: implications for human disease

Abstract

Nuclear factor (erythroid derived)-2 like 2 (NFE2L2), also known as nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), is a ubiquitous transcription factor essential for protecting cells and tissues from oxidative stress-induced injury. Positional cloning and studies with Nrf2 knockout mice have identified important roles for this transcription factor in disease phenotypes for many organ systems. Studies have also characterized the means through which human Nrf2 is regulated and the mechanisms of interaction with antioxidant response elements (ARE) in promoters of effector genes. Moreover, single nucleotide polymorphisms (SNPs) in Nrf2 have been identified and evaluated for effects on gene expression and function, and translational investigations have sought to determine whether loss of function SNPs associate with disease progression. In this review, we present 1) an overview of the human Nrf2 gene and protein domain, 2) identification of genetic mutations in Nrf2 and associations of the mutations with multiple diseases, and 3) the role of somatic mutations in Nrf2 in diseases, primarily various cancers.

Keywords: Antioxidant response element; Complex disease; Genetic; Genome-wide association; Mouse; Mutations; Promoter; Somatic.

Figure 1.. Human NRF2 gene, mRNA, and protein.

Human NRF2 located on human chromosome 2 harbors 5 exons, and transcript (variant 1, 2856 bp) encodes a protein containing 605 amino acid residues. NRF2 protein is consisted of 6 highly conserved Neh domains. At-risk genetic variations in the promoter, exon 1, and introns of NRF2 are depicted by red dots. Somatic, non-synonymous mutations clustered in Neh2 domain associated with various cancers are marked as yellow dots.

Figure 2.. Haploview linkage disequilibrium (LD) plot of NRF2 SNPs.

(A) Linkage disequilibrium (LD) data for NRF2 SNPs acquired from Haploview [http://www.broadinstitute.org] and other publications [24]. Intensity of shading and numerical values indicate level (or strength) of linkage between two comparison loci and patterned squares indicate loci with insufficient linkage data, while low LD values can indicate regions of homologous recombination or crossover during mitosis. Three proximal NRF2 promoter SNPs (rs6721961, rs6706649, and rs35652124) in the red rectangles are involved in a variety of diseases detailed in this review (Details in Table 3), and ordered relative to the transcription start site (TSS). UTR = untranslated region. Refer to NC_000002.12 for chromosome 2 location. Referred to NM_006164 (transcript variant 1) for promoter and exon SNP location. (B) Nrf2 SNP haplotypes blocks modified from http://snpinfo.niehs.nih.gov/snpinfo/snptag.htm. Ten representative individuals from ethnic groups (Asian, African, European and African Americans) are shown for color-coded haplogroup blocks. Blue is the major allele or homozygous common genotype, red is the minor allele or homozygous rare genotype, and yellow is heterozygous at that locus. Gray signifies missing data at this locus. Arrows denote individual tagging SNPs as shown at top in linkage disequilibrium (LD) bins.

Figure 2.. Haploview linkage disequilibrium (LD) plot of NRF2 SNPs.

(A) Linkage disequilibrium (LD) data for NRF2 SNPs acquired from Haploview [http://www.broadinstitute.org] and other publications [24]. Intensity of shading and numerical values indicate level (or strength) of linkage between two comparison loci and patterned squares indicate loci with insufficient linkage data, while low LD values can indicate regions of homologous recombination or crossover during mitosis. Three proximal NRF2 promoter SNPs (rs6721961, rs6706649, and rs35652124) in the red rectangles are involved in a variety of diseases detailed in this review (Details in Table 3), and ordered relative to the transcription start site (TSS). UTR = untranslated region. Refer to NC_000002.12 for chromosome 2 location. Referred to NM_006164 (transcript variant 1) for promoter and exon SNP location. (B) Nrf2 SNP haplotypes blocks modified from http://snpinfo.niehs.nih.gov/snpinfo/snptag.htm. Ten representative individuals from ethnic groups (Asian, African, European and African Americans) are shown for color-coded haplogroup blocks. Blue is the major allele or homozygous common genotype, red is the minor allele or homozygous rare genotype, and yellow is heterozygous at that locus. Gray signifies missing data at this locus. Arrows denote individual tagging SNPs as shown at top in linkage disequilibrium (LD) bins.