Dataset Information

Comprehensive assessment of genetic sequence variants in the antioxidant 'master regulator' NRF2 in idiopathic Parkinson's disease.

ABSTRACT: Parkinson's disease (PD) is a complex neurodegenerative disorder influenced by a combination of genetic and environmental factors. The molecular mechanisms that underlie PD are unknown; however, oxidative stress and impairment of antioxidant defence mechanisms have been implicated as major contributors to disease pathogenesis. Previously, we have reported a PD patient-derived cellular model generated from biopsies of the olfactory mucosa, termed hONS cells, in which the NRF2-mediated antioxidant response pathway genes were among the most differentially-expressed. To date, few studies have examined the role of the NRF2 encoding gene, NFE2L2, and PD. In this study, we comprehensibly assessed whether rare and common NFE2L2 genetic variations modify susceptibility to PD using a large Australian case-control sample (PD=1338, controls=1379). We employed a haplotype-tagging approach that identified an association with the tagging SNP rs2364725 and PD (OR = 0.849 (0.760-0.948), P = 0.004). Further genetic screening in hONS cell lines produced no obvious pathogenic variants in the coding regions of NFE2L2. Finally, we investigated the relationship between xenobiotic exposures and NRF2 function, through gene-environment interactions, between NFE2L2 SNPs and smoking or pesticide exposure. Our results demonstrated a significant interaction between rs2706110 and pesticide exposure (OR = 0.597 (0.393-0.900), P = 0.014). In addition, we were able to identify some age-at-onset modifying SNPs and replicate an 'early-onset' haplotype that contains a previously identified 'functional promoter' SNP (rs6721961). Our results suggest a role of NFE2L2 genetic variants in modifying PD susceptibility and onset. Our findings also support the utility of testing gene-environment interactions in genetic studies of PD.

SUBMITTER: Todorovic M

PROVIDER: S-EPMC4444110 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Comprehensive assessment of genetic sequence variants in the antioxidant 'master regulator' NRF2 in idiopathic Parkinson's disease.

Todorovic Michael M Newman Jeremy R B JR Shan Jianguo J Bentley Steven S Wood Stephen A SA Silburn Peter A PA Mellick George D GD

PloS one 20150526 5

Parkinson's disease (PD) is a complex neurodegenerative disorder influenced by a combination of genetic and environmental factors. The molecular mechanisms that underlie PD are unknown; however, oxidative stress and impairment of antioxidant defence mechanisms have been implicated as major contributors to disease pathogenesis. Previously, we have reported a PD patient-derived cellular model generated from biopsies of the olfactory mucosa, termed hONS cells, in which the NRF2-mediated antioxidant ...[more]

PMID: 26010367

Similar Datasets

Project description:BACKGROUND: The transcription factor Nrf2, encoded by the NFE2L2 gene, is an important regulator of the cellular protection against oxidative stress. Parkinson's disease is a neurodegenerative disease highly associated with oxidative stress. In a previously published study, we reported associations of NFE2L2 haplotypes with risk and age at onset of idiopathic Parkinson's disease in a Swedish discovery material and a Polish replication material. Here, we have extended the replication study and performed meta-analyses including the Polish material and four new independent European patient-control materials. Furthermore, all SNPs included in the haplotype windows were investigated individually for associations with Parkinson's disease in meta-analyses including all six materials. METHODS: Totally 1038 patients and 1600 control subjects were studied. Based on previous NFE2L2 haplotype associations with Parkinson's disease, five NFE2L2 tag SNPs were genotyped by allelic discrimination and three functional NFE2L2 promoter SNPs were genotyped by sequencing. The impact of individual SNPs and haplotypes on risk and age at onset of Parkinson's disease were investigated in each material individually and in meta-analyses of the obtained results. RESULTS: Meta-analyses of NFE2L2 haplotypes showed association of haplotype GAGCAAAA, including the fully functional promoter haplotype AGC, with decreased risk (OR?=?0.8 per allele, p?=?0.012) and delayed onset (+1.1 years per allele, p?=?0.048) of Parkinson's disease. These results support the previously observed protective effect of this haplotype in the first study. Further, meta-analyses of the SNPs included in the haplotypes revealed four NFE2L2 SNPs associated with age at onset of Parkinson's disease (rs7557529 G?>?A, -1.0 years per allele, p?=?0.042; rs35652124 A?>?G, -1.1 years per allele, p?=?0.045; rs2886161 A?>?G, -1.2 years per allele, p?=?0.021; rs1806649 G?>?A, +1.2 years per allele, p?=?0.029). One of these (rs35652124) is a functional SNP located in the NFE2L2 promoter. No individual SNP was associated with risk of Parkinson's disease. CONCLUSION: Our results support the hypothesis that variation in the NFE2L2 gene, encoding a central protein in the cellular protection against oxidative stress, may contribute to the pathogenesis of Parkinson's disease. Functional studies are now needed to explore these results further.

Dataset Information

Comprehensive assessment of genetic sequence variants in the antioxidant 'master regulator' NRF2 in idiopathic Parkinson's disease.

Publications

Comprehensive assessment of genetic sequence variants in the antioxidant 'master regulator' NRF2 in idiopathic Parkinson's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets