Abstract
BackgroundThe 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.MethodsTotally 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.ResultsMeta-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.ConclusionOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-014-0131-4) contains supplementary material, which is available to authorized users.
Highlights
The transcription factor Nuclear factor erythroid 2 related factor 2 (Nrf2), encoded by the NF-E2-like 2 (NFE2L2) gene, is an important regulator of the cellular protection against oxidative stress
One study has shown that an increased oxidative stress observed in olfactory neurosphere-derived cells from Parkinson? s disease (PD) patients could be restored by activation of Nrf2 with sulforaphane [12] and curcumin has been shown to protect DAergic SH-SY5Y neurons from 6Hydroxydopamine toxicity [13]
We previously reported that a haplotype in the NFE2L2 gene, GAAAA consisting of five tag single nucleotide polymorphisms (SNPs), was associated with delayed age at onset (AAO) in a Swedish discovery material and with decreased risk of PD in an independent Polish replication material [23]
Summary
The transcription factor Nrf, encoded by the NFE2L2 gene, is an important regulator of the cellular protection against oxidative stress. We have extended the replication study and performed meta-analyses including the Polish material and four new independent European patient-control materials. Nuclear factor erythroid 2 (NF-E2) related factor 2 (Nrf2), a transcription factor encoded by the NF-E2-like 2 (NFE2L2) gene, has a key role in the cellular protection against oxidative and electrophilic insults [4]. One study has shown that an increased oxidative stress observed in olfactory neurosphere-derived cells from PD patients could be restored by activation of Nrf with sulforaphane [12] and curcumin has been shown to protect DAergic SH-SY5Y neurons from 6Hydroxydopamine toxicity [13]. Another study has shown that upregulation of Nrf using potent synthetic Nrf activators protects DAergic neurons from degeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD [14]
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