Cargando…
Comprehensive Assessment of Genetic Sequence Variants in the Antioxidant ‘Master Regulator’ Nrf2 in Idiopathic Parkinson’s Disease
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 contribut...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444110/ https://www.ncbi.nlm.nih.gov/pubmed/26010367 http://dx.doi.org/10.1371/journal.pone.0128030 |
_version_ | 1782373083864104960 |
---|---|
author | Todorovic, Michael Newman, Jeremy R. B. Shan, Jianguo Bentley, Steven Wood, Stephen A. Silburn, Peter A. Mellick, George D. |
author_facet | Todorovic, Michael Newman, Jeremy R. B. Shan, Jianguo Bentley, Steven Wood, Stephen A. Silburn, Peter A. Mellick, George D. |
author_sort | Todorovic, Michael |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4444110 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-44441102015-06-16 Comprehensive Assessment of Genetic Sequence Variants in the Antioxidant ‘Master Regulator’ Nrf2 in Idiopathic Parkinson’s Disease Todorovic, Michael Newman, Jeremy R. B. Shan, Jianguo Bentley, Steven Wood, Stephen A. Silburn, Peter A. Mellick, George D. PLoS One Research Article 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. Public Library of Science 2015-05-26 /pmc/articles/PMC4444110/ /pubmed/26010367 http://dx.doi.org/10.1371/journal.pone.0128030 Text en © 2015 Todorovic et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Todorovic, Michael Newman, Jeremy R. B. Shan, Jianguo Bentley, Steven Wood, Stephen A. Silburn, Peter A. Mellick, George D. Comprehensive Assessment of Genetic Sequence Variants in the Antioxidant ‘Master Regulator’ Nrf2 in Idiopathic Parkinson’s Disease |
title | Comprehensive Assessment of Genetic Sequence Variants in the Antioxidant ‘Master Regulator’ Nrf2 in Idiopathic Parkinson’s Disease |
title_full | Comprehensive Assessment of Genetic Sequence Variants in the Antioxidant ‘Master Regulator’ Nrf2 in Idiopathic Parkinson’s Disease |
title_fullStr | Comprehensive Assessment of Genetic Sequence Variants in the Antioxidant ‘Master Regulator’ Nrf2 in Idiopathic Parkinson’s Disease |
title_full_unstemmed | Comprehensive Assessment of Genetic Sequence Variants in the Antioxidant ‘Master Regulator’ Nrf2 in Idiopathic Parkinson’s Disease |
title_short | Comprehensive Assessment of Genetic Sequence Variants in the Antioxidant ‘Master Regulator’ Nrf2 in Idiopathic Parkinson’s Disease |
title_sort | comprehensive assessment of genetic sequence variants in the antioxidant ‘master regulator’ nrf2 in idiopathic parkinson’s disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4444110/ https://www.ncbi.nlm.nih.gov/pubmed/26010367 http://dx.doi.org/10.1371/journal.pone.0128030 |
work_keys_str_mv | AT todorovicmichael comprehensiveassessmentofgeneticsequencevariantsintheantioxidantmasterregulatornrf2inidiopathicparkinsonsdisease AT newmanjeremyrb comprehensiveassessmentofgeneticsequencevariantsintheantioxidantmasterregulatornrf2inidiopathicparkinsonsdisease AT shanjianguo comprehensiveassessmentofgeneticsequencevariantsintheantioxidantmasterregulatornrf2inidiopathicparkinsonsdisease AT bentleysteven comprehensiveassessmentofgeneticsequencevariantsintheantioxidantmasterregulatornrf2inidiopathicparkinsonsdisease AT woodstephena comprehensiveassessmentofgeneticsequencevariantsintheantioxidantmasterregulatornrf2inidiopathicparkinsonsdisease AT silburnpetera comprehensiveassessmentofgeneticsequencevariantsintheantioxidantmasterregulatornrf2inidiopathicparkinsonsdisease AT mellickgeorged comprehensiveassessmentofgeneticsequencevariantsintheantioxidantmasterregulatornrf2inidiopathicparkinsonsdisease |