von Otter, M;
Bergström, P;
Quattrone, A;
De Marco, EV;
Annesi, G;
Söderkvist, P;
Wettinger, SB;
... Zetterberg, H; + view all
(2014)
Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson's disease - a multicenter study.
BMC Medical Genetics
, 15
, Article 131. 10.1186/s12881-014-0131-4.
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Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson’s disease – a multicenter study.pdf Download (546kB) | Preview |
Abstract
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.
| Type: | Article |
|---|---|
| Title: | Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson's disease - a multicenter study |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s12881-014-0131-4 |
| Publisher version: | http://dx.doi.org/10.1186/s12881-014-0131-4 |
| Language: | English |
| Additional information: | Copyright © von Otter et al.; licensee BioMed Central. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
| Keywords: | Age of Onset, Aged, Aged, 80 and over, Alleles, Case-Control Studies, Demography, Female, Genome-Wide Association Study, Genotyping Techniques, Haplotypes, Humans, Male, Middle Aged, NF-E2-Related Factor 2, Oxidative Stress, Parkinson Disease, Poland, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Risk Factors, Sequence Analysis, DNA, Sweden |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1459626 |
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