Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson's disease: a multicenter study
Journal article, 2014

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.

Nrf2

Haplotype

Multicenter

PD

Parkinson s disease

Risk factor

Meta-analysis

SNP

NFE2L2

Author

Malin von Otter

University of Gothenburg

Petra Bergström

University of Gothenburg

Aldo Quattrone

Consiglo Nazionale Delle Richerche

Magna Græcia University

Elvira De Marco

Consiglo Nazionale Delle Richerche

Grazia Annesi

Consiglo Nazionale Delle Richerche

Peter Söderkvist

Linköping University

Stephanie Wettinger

University of Malta

Marek Drozdzik

Pomeranian Medical University in Szczecin

Monika Bialecka

Pomeranian Medical University in Szczecin

Hans Nissbrandt

University of Gothenburg

Christine Klein

Universitaet Zu Lübeck

Michael Nilsson

University of Gothenburg

Ola Hammarsten

University of Gothenburg

Staffan Nilsson

University of Gothenburg

Chalmers, Mathematical Sciences, Mathematical Statistics

Henrik Zetterberg

University of Gothenburg

BMC Medical Genetics

14712350 (eISSN)

Vol. 15 1 artikel nr 131- 131

Subject Categories

Neurosciences

Areas of Advance

Life Science Engineering (2010-2018)

DOI

10.1186/s12881-014-0131-4

PubMed

25496089

More information

Latest update

9/6/2018 1