Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson’s disease – a multicenter study

BMC Medical Genetics

Henrik Zetterberg⁷  Staffan Nilsson⁸  Ola Hammarsten⁹  Michael Nilsson^1,13  Christine Klein⁵  Hans Nissbrandt^1,10  Monika Bialecka⁶  Marek Drozdzik⁶  Stephanie Bezzina Wettinger^1,12  Peter Söderkvist²  Grazia Annesi³  Elvira Valeria De Marco¹  Aldo Quattrone⁴  Petra Bergström^1,11  Malin von Otter^1,11 

[1] Institute of Neurological Sciences, National Research Council, Cosenza, Italy;Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, SE-581 85, Sweden;Institute of Molecular Bioimaging and Physiology, Section of Germaneto, National Research Council, Catanzaro, Italy;Neuroimaging Research Unit, Institute of Molecular Bioimaging and Physiology, National Research Council, Catanzaro, Italy;Institute of Neurogenetics, University of Luebeck, Luebeck, Germany;Department of Pharmacology, Pomeranian Medical University, Powstancow Wlkp. 72, Szczecin 70-111, Poland;UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK;Institute of Mathematical Sciences, Department of Mathematical Statistics, Chalmers University of Technology, Chalmers tvärgata 3, Gothenburg, 412 96, Sweden;Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy at the University of Gothenburg, Bruna Stråket 16, Gothenburg, 413 45, Sweden;Institute of Neuroscience and Physiology, Department of Pharmacology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, 405 30, Sweden;Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Blå stråket 15, Gothenburg, 413 45, Sweden;Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta;Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia

关键词: Risk factor;    Haplotype;    SNP;    Multicenter;    Meta-analysis;    NFE2L2;    Nrf2;    PD;    Parkinson’s disease;   

Others  :  1090088
DOI  :  10.1186/s12881-014-0131-4

 received in 2014-08-26, accepted in 2014-12-01,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 von Otter et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

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