Association of Nrf2-encoding NFE2L2 haplotypes with Parkinson's disease

Malin Von Otter,Ola Hammarsten,Henrik Zetterberg,Anna Håkansson,Dragana Celojevic,Kaj Blennow,Hans Nissbrandt,Mateusz Kurzawski,Petra Bergström,Monika Bialecka,Marek Drozdzik,Sara Landgren,Michael Nilsson,Staffan Nilsson

doi:10.1186/1471-2350-11-36

Abstract

BackgroundOxidative stress is heavily implicated in the pathogenic process of Parkinson's disease. Varying capacity to detoxify radical oxygen species through induction of phase II antioxidant enzymes in substantia nigra may influence disease risk. Here, we hypothesize that variation in NFE2L2 and KEAP1, the genes encoding the two major regulators of the phase II response, may affect the risk of Parkinson's disease.MethodsThe study included a Swedish discovery case-control material (165 cases and 190 controls) and a Polish replication case-control material (192 cases and 192 controls). Eight tag single nucleotide polymorphisms representing the variation in NFE2L2 and three representing the variation in KEAP1 were chosen using HapMap data and were genotyped using TaqMan Allelic Discrimination.ResultsWe identified a protective NFE2L2 haplotype in both of our European case-control materials. Each haplotype allele was associated with five years later age at onset of the disease (p = 0.001) in the Swedish material, and decreased risk of PD (p = 2 × 10-6), with an odds ratio of 0.4 (95% CI 0.3-0.6) for heterozygous and 0.2 (95% CI 0.1-0.4) for homozygous carriers, in the Polish material. The identified haplotype includes a functional promoter haplotype previously associated with high transcriptional activity. Genetic variation in KEAP1 did not show any associations.ConclusionThese data suggest that variation in NFE2L2 modifies the Parkinson's disease process and provide another link between oxidative stress and neurodegeneration.

Highlights

Oxidative stress is heavily implicated in the pathogenic process of Parkinson’s disease
Family history of Parkinson’s disease (PD) and ever smoking as significantly relevant covariates for the analyses of association with disease risk
History of PD alone was identified as a significant covariate in analyses of association with age at onset (AAO)

Summary

Introduction

Oxidative stress is heavily implicated in the pathogenic process of Parkinson’s disease. In PD brain specimens, signs of oxidative stress are especially prominent in the substantia nigra This may be the result of combined presence of a high dopamine metabolism generating reactive oxygen species (ROS), low levels of antioxidant glutathione and increased levels of iron catalyzing ROS. Upon exposure to oxidative stress, xenobiotics, or electrophilic metabolites of phase I enzymes, repression of Nrf by Keap ubiquitination is disrupted and newly produced Nrf enters the nucleus [14]. There, it forms heterodimers with other transcription regulators, such as small Maf proteins, and induces the expression of antioxidant phase II genes through interaction with the antioxidant responsive element (ARE) in the promoter of these genes [15,16]. Upregulation of Nrf activity in astrocytes delays motor neuron degeneration in a mouse model of familial amyotrophic lateral sclerosis [23]

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