Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson s disease a multicenter study
2014 (English)In: BMC Medical Genetics, ISSN 1471-2350, Vol. 15, no 131Article in journal (Refereed) Published
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 greater than A, -1.0 years per allele, p = 0.042; rs35652124 A greater than G, -1.1 years per allele, p = 0.045; rs2886161 A greater than G, -1.2 years per allele, p = 0.021; rs1806649 G greater than 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. Conclusion: 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.
Place, publisher, year, edition, pages
BioMed Central / Springer Verlag (Germany) , 2014. Vol. 15, no 131
Parkinson s disease; PD; Nrf2; NFE2L2; Meta-analysis; Multicenter; SNP; Haplotype; Risk factor
IdentifiersURN: urn:nbn:se:liu:diva-114256DOI: 10.1186/s12881-014-0131-4ISI: 000348159800001PubMedID: 25496089OAI: oai:DiVA.org:liu-114256DiVA: diva2:788614
Funding Agencies|Swedish Research Council; Knut and Alice Wallenberg Foundation; Sahlgrenska University Hospital; West Sweden RUN fundings; Edith Jacobsson Foundation; Axel Linders Foundation; Gteborg Medical Society; Swedish Medical Society; Swedish Brain Power; Stiftelsen fr Gamla Tjnarinnor; Swedish Parkinson Foundation; Foundation for Parkinson Research at Linkping University (Stiftelsen fr Parkinsonforskning), Sweden; Gun and Bertil Stohne s Foundation; hln Foundation; Alzheimer s Foundation, Sweden; Assar Gabrielsson Foundation; Swedish Cancer Foundation; Swedish Pain Foundation; Herman and Lilly Schilling Foundation2015-02-162015-02-162015-02-26