title: 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.
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Todorovic
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
authors.forename: Jeremy R B
authors.initials: JR
authors.lastname: Newman
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Shan
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Bentley
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Wood
authors.affiliation: Asia-Pacific Centre for Neuromodulation, UQCCR, University of Queensland, Herston, Queensland, Australia.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Silburn
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia; Asia-Pacific Centre for Neuromodulation, UQCCR, University of Queensland, Herston, Queensland, Australia.
authors.forename: George D
authors.initials: GD
authors.lastname: Mellick
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D016022:Case-Control Studies; D002460:Cell Line; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human