alpha-Synuclein and Parkinson disease susceptibility.
BACKGROUND
Mutations in the alpha-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 <or= 0.003), with significant pairwise values for linkage disequilibrium (D' >or= 0.74, r (2) >or= 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.
Winkler
S
S
Department of Neurology, University of Lübeck; Ratzeburger Allee 160, 23538 Lübeck, Germany.
Hagenah
J
J
Lincoln
S
S
Heckman
M
M
Haugarvoll
K
K
Lohmann-Hedrich
K
K
Kostic
V
V
Farrer
M
M
Klein
C
C
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D051844:alpha-Synuclein / Q000235:genetics*
D005819:Genetic Markers; D051844:alpha-Synuclein