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

Journal article
Authors Malin von Otter
Sara Landgren
Staffan Nilsson
Dragana Celojevic
Petra Bergström
Anna Håkansson
Hans Nissbrandt
Marek Drozdzik
Monika Bialecka
Mateusz Kurzawski
Kaj Blennow
Michael Nilsson
Ola Hammarsten
Henrik Zetterberg
Published in BMC medical genetics
Volume 11
Pages 36
ISSN 1471-2350
Publication year 2010
Published at Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation
Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Department of Mathematical Sciences, Mathematical Statistics
Institute of Biomedicine
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Institute of Neuroscience and Physiology, Department of Pharmacology
Pages 36
Language en
Links dx.doi.org/10.1186/1471-2350-11-36
Subject categories Physiology, Psychiatry

Abstract

BACKGROUND: Oxidative 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. METHODS: The 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. RESULTS: We 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 x 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. CONCLUSION: These data suggest that variation in NFE2L2 modifies the Parkinson's disease process and provide another link between oxidative stress and neurodegeneration.

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