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-Synuclein and Parkinson disease susceptibility

From the Departments of Neurology (S.W., J.H., K.L.-H., C.K.) and Human Genetics (S.W., K.L.-H., C.K.), University of Lübeck, Lübeck, Germany; Department of Neuroscience, Mayo Clinic, Jacksonville, FL (S.L., M.H., K.H., M.F.); and Department of Neurology, University of Belgrade, Belgrade, Serbia and Montenegro (V.K.).

Address correspondence and reprint requests to Dr. Christine Klein, Department of Neurology, University of Lübeck; Ratzeburger Allee 160, 23538 Lübeck, Germany christine.klein{at}neuro.uni-luebeck.de

Background: Mutations in the -synuclein (SNCA) gene have been shown to be responsible for a rare familial form of Parkinson disease (PD). Furthermore, polymorphic variants in multiple regions of the gene have been associated with susceptibility to idiopathic PD in different populations.

Objective: To evaluate and to confirm the role of SNCA variants in PD pathogenesis.

Methods: We included 667 subjects (397 cases with idiopathic PD and 270 healthy, ethnically matched controls) of Northern Central and Southeastern European origin. We analyzed genotypes at 14 markers spanning the SNCA locus and its major haplotype blocks and conducted a haplotype analysis for four promoter markers including the microsatellite marker Rep1.

Results: The three single nucleotide polymorphisms (SNPs) of the promoter region (rs2583988, rs2619364, rs2619363) and a SNP in the 3'UTR (rs356165) of the SNCA gene showed the greatest evidence for an association with PD (p 0.003), with significant pairwise values for linkage disequilibrium (D' 0.74, r ² 0.29). The promoter haplotype "261-T-G-T" (Rep1-rs2583988-rs2619364-rs2619363) was associated with disease (p = 0.032). The most significant association with PD was generated by excluding Rep1 (p = 0.008). This association remained significant when analyzing the Serbian patients separately and was of borderline significance for the German patients.

Conclusions: Our findings confirm that genetic variability within the SNCA locus is associated with susceptibility to idiopathic Parkinson disease (PD). We found evidence for disease association with single nucleotide polymorphisms at both the 5' and the 3' end of the gene with pairwise linkage disequilibrium between them. The association was independent of the Rep1 status, and one major SNCA promoter haplotype class seems to be associated with PD susceptibility.

GLOSSARY: SNCA = -synuclein; CI = confidence interval; HT = haplotype-tagging; LD = linkage disequilibrium; OR = odds ratio; PD = Parkinson disease; SNP = single nucleotide polymorphism.

Supplemental data at www.neurology.org

e-Pub ahead of print on September 12, 2007, at www.neurology.org.

Supported by a grant from the Deutsche Forschungsgemeinschaft, the PD Foundation/National Parkinson Foundation, the Bundesministerium für Bildung und Forschung, and the University Lübeck (all to C.K.). C.K. is supported by the VolkswagenStiftung. The Morris K. Udall Center for Excellence (NIH P50 NS40256) supports Parkinson disease research at Mayo Clinic.

Disclosure: The authors report no conflicts of interest.

Received February 15, 2007. Accepted in final form May 21, 2007.

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