Genetic associations of Nrf2-encoding variants with Parkinson's disease - a multicenter study

Abstract

Background: The transcription factor Nrf2, encoded by the 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 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 haplotype associations with Parkinson's disease, five tag SNPs were genotyped by allelic discrimination and three functional 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 haplotypes showed association of haplotype GAAAA, 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 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 promoter. No individual SNP was associated with risk of Parkinson's disease. Conclusion: Our results support the hypothesis that variation in the 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.