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Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson's disease: a multicenter study

Artikel i vetenskaplig tidskrift
Författare Malin von Otter
Petra Bergström
Aldo Quattrone
Elvira De Marco
Grazia Annesi
Peter Söderkvist
Stephanie Wettinger
Marek Drozdzik
Monika Bialecka
Hans Nissbrandt
Christine Klein
Michael Nilsson
Ola Hammarsten
Staffan Nilsson
Henrik Zetterberg
Publicerad i BMC medical genetics
Volym 15
Sidor artikel nr 131
ISSN 1471-2350
Publiceringsår 2014
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för klinisk neurovetenskap och rehabilitering
Institutionen för biomedicin, avdelningen för klinisk kemi och transfusionsmedicin
Institutionen för matematiska vetenskaper, matematisk statistik
Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Institutionen för neurovetenskap och fysiologi, sektionen för farmakologi
Sidor artikel nr 131
Språk en
Länkar dx.doi.org/10.1186/s12881-014-0131-...
https://gup.ub.gu.se/file/149924
Ämnesord Parkinson s disease; PD; Nrf2; NFE2L2; Meta-analysis; Multicenter; SNP; Haplotype; Risk factor
Ämneskategorier Neurokemi

Sammanfattning

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 > 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.

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.

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