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NFE2L2, PPARGC1?, and pesticides and Parkinson's disease risk and progression.

ABSTRACT: OBJECTIVE:To investigate three expression-altering NFE2L2 SNPs and four PPARGC1? previously implicated SNPs and pesticides on Parkinson's disease (PD) risk and symptom progression. METHODS:In 472 PD patients and 532 population-based controls, we examined variants and their interactions with maneb and paraquat (MB/PQ) pesticide exposure on PD onset (logistic regression) and progression of motor symptoms and cognitive decline (n?=?192; linear repeated measures). RESULTS:NFE2L2 rs6721961 T allele was associated with a reduced risk of PD (OR?=?0.70, 95% CI?=?0.53, 0.94) and slower cognitive decline (??=?0.095; p?=?0.0004). None of the PPARGC1? SNPs were marginally associated with PD risk. We estimate statistical interactions between MB/PQ and PPARGC1? rs6821591 (interaction p?=?0.009) and rs8192678 (interaction p?=?0.05), such that those with high exposure and the variant allele were at an increased risk of PD (OR???1.30, p???0.05). PPARGC1? rs6821591 was also associated with faster motor symptom progression as measured with the UPDRS-III (??=?0.234; p?=?0.001). CONCLUSION:Our study provides support for the involvement of both NFE2L2 and PPARGC1? in PD susceptibility and progression, marginally and through pathways involving MB/PQ exposure.

SUBMITTER: Paul KC

PROVIDER: S-EPMC5994195 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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NFE2L2, PPARGC1α, and pesticides and Parkinson's disease risk and progression.

Paul Kimberly C KC Sinsheimer Janet S JS Cockburn Myles M Bronstein Jeff M JM Bordelon Yvette Y Ritz Beate B

Mechanisms of ageing and development 20180406

<h4>Objective</h4>To investigate three expression-altering NFE2L2 SNPs and four PPARGC1α previously implicated SNPs and pesticides on Parkinson's disease (PD) risk and symptom progression.<h4>Methods</h4>In 472 PD patients and 532 population-based controls, we examined variants and their interactions with maneb and paraquat (MB/PQ) pesticide exposure on PD onset (logistic regression) and progression of motor symptoms and cognitive decline (n = 192; linear repeated measures).<h4>Results</h4>NFE2L ...[more]

PMID: 29630901

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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.

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NFE2L2, PPARGC1?, and pesticides and Parkinson's disease risk and progression.

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NFE2L2, PPARGC1α, and pesticides and Parkinson's disease risk and progression.

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