title: Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson's disease - a multicenter study.
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.
  
  
  CONCLUSIONS
  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.
authors.forename: Malin
authors.initials: M
authors.lastname: von Otter
authors.forename: Petra
authors.initials: P
authors.lastname: Bergström
authors.forename: Aldo
authors.initials: A
authors.lastname: Quattrone
authors.forename: Elvira Valeria
authors.initials: EV
authors.lastname: De Marco
authors.forename: Grazia
authors.initials: G
authors.lastname: Annesi
authors.forename: Peter
authors.initials: P
authors.lastname: Söderkvist
authors.forename: Stephanie Bezzina
authors.initials: SB
authors.lastname: Wettinger
authors.forename: Marek
authors.initials: M
authors.lastname: Drozdzik
authors.forename: Monika
authors.initials: M
authors.lastname: Bialecka
authors.forename: Hans
authors.initials: H
authors.lastname: Nissbrandt
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.forename: Michael
authors.initials: M
authors.lastname: Nilsson
authors.forename: Ola
authors.initials: O
authors.lastname: Hammarsten
authors.forename: Staffan
authors.initials: S
authors.lastname: Nilsson
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D003710:Demography; D005260:Female; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D010300:Parkinson Disease / Q000453:epidemiology* / Q000235:genetics*; D011044:Poland / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D013548:Sweden / Q000453:epidemiology
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human