Neuroscience & Medicine, 2013, 4, 208-214
Published Online December 2013 (http://www.scirp.org/journal/nm)
http://dx.doi.org/10.4236/nm.2013.44032
Open Access NM
Polymorphisms in the SNCA Gene: Association with the
Risk of Development of the Sporadic Form of Parkinson’s
Disease and the Level of SNCA Gene Expression in
Peripheral Blood of Patients from Russia
Anelya Kh. Alieva1*, Maria I. Shadrina1, Elena V. Filatova1, Vera V. Ustinova1,
Ekaterina Yu Fedotova2, Alexey V. Karabanov2, Sergey N. Illarioshkin2, Petr A. Slominsky1
1Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia; 2Research Centre of Neurology, Russian Academy
of Medical Sciences, Moscow, Russia.
Received August 20th, 2013; revised September 18th, 2013; accepted October 15th, 2013
Copyright © 2013 Anelya Kh. Alieva et al. This is an open access article distributed under the Creative Commons Attribution Li-
cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Parkinson’s disease (PD) is one of the most common human neurodegenerative disorders caused by the loss of dopa-
minergic neurons in the brain. The α-synuclein (SNCA) gene is one of the most studied genes involved in the patho-
genesis of PD. In our study, we conducted a genetic analysis of promoter and intron single-nucleotide polymorphisms
(SNPs) in the SNCA gene. We also analyzed the association of genotypes of these SNPs with expression levels of SNCA
mRNA. One of four SNPs in the SNCA gene, and the rs2736990 polymorphism, associates with the risk of the sporadic
form of PD in Russian population. The risk of PD was increased almost twofold in carriers of allele C (odds ratios = 1.9,
95% confidence interval: 1.24 - 2.91, p = 0.003). However, no association was found between any of the genotypes of
SNPs tested (rs2583988, rs2619363, rs2619364 and rs2736990) and alterations in SNCA levels. Our findings support
the hypothesis that the rs2736990 polymorphism is associated with PD. SNPs rs2583988, rs2619363 and rs2619364 in
the promoter region of the SNCA gene themselves do not significantly influence the expression of SNCA. Most likely,
SNCA gene expression is a very complex process that is affected by different genetic and epigenetic factors.
Keywords: Parkinson’s Disease; Expression Analysis; SNCA; SNP
1. Introduction
Parkinson’s disease (PD) is one of the most common
human neurodegenerative disorders after Alzheimer’s
disease. PD is morphologically characterized by progres-
sive loss of dopaminergic neurons and in some cases by
formation of fibrillar inclusions (Lewy bodies) with α-
synuclein (SNCA) as its main component [1]. SNCA acts
as a molecular chaperone and regulates protein-protein
interactions in cells [2]. According to the latest data,
SNCA is required for the normal operation of a pre-syn-
aptic complex by participating in the cyclic release of
dopamine from the presynaptic vesicles [3-5]. SNCA was
the first gene whose association with PD has been shown
[6]. Currently, the SNCA gene is one of the most studied
genes involved in the pathogenesis of PD. Several point
mutations in the SNCA gene and duplications and tripli-
cations of the genomic region containing SNCA were
revealed. They are very rare and lead to the development
of an autosomal dominant form of PD [7-11].
To date, a number of single-nucleotide polymorphisms
(SNPs) in SNCA associated with a risk of the sporadic
form of the disease have been revealed. According to
genome-wide association studies (GWASs), more than
five polymorphic variants were found to be associated
with the risk of development of PD. One of the first of
these SNPs identified in a genome-wide study was
rs2736990. An association of this polymorphism with the
risk of PD in patients from Europe and North America
has been shown [12,13]. However, the risk of disease
development did not exceed odds ratio (OR) = 1.4. Thus,
further verification of the results of GWASs in other
population samples is required.
*Corresponding author.

Polymorphisms in the SNCA Gene: Association with the Risk of Development of the Sporadic Form of
Parkinson’s Disease and the Level of SNCA Gene Expression in Peripheral Blood of Patients from Russia
209
Furthermore, polymorphic microsatellite Rep1 was
found in the promoter region of 10 kb upstream of the
SNCA transcription start site [14-16]. One of the micro-
satellite polymorphic variants, Rep1-261, has been asso-
ciated with an increase in mRNA levels of SNCA in ex-
periments with transgenic mice [17]. At the same time,
the presence of the Rep1-259 allele has been demon-
strated to correlate with a low level of SNCA mRNA in
post mortem brain tissues of patients with PD [18]. It was
shown that Rep1 was associated with rs2583988, rs2619363
and rs2619364, and that these polymorphic variants were
in a strong linkage disequilibrium (LD: r2 = 0.99, D’ =
1.00) [19,20]. In studies of patients with PD from Europe
(Belgium, Germany and Serbia), an association of these
polymorphisms with the risk of PD was identified [20-
22].
Thereby, the aim of our study was to assess the role of
rs2736990, rs2583988, rs2619363 and rs2619364 in the
determination of genetic risk of development of PD in
the Russian population. In addition, an analysis of the
association between these SNPs and levels of SNCA
transcripts in the peripheral blood of patients with PD
from Russia was performed.
2. Methods
2.1. Patients
All patients (Russians residing in the European part of
Russia) were diagnosed with PD at the Research Center
of Neurology, Russian Academy of Medical Sciences
(RAMS). All patients with PD were selected and studied
according to the international Unified Parkinson’s Dis-
ease Rating Scale (UPDRS) and Hoehn and Yahr scores
[23,24]. The diagnosis of PD was based on the UK PD
Brain Bank Criteria [25]. In this work, two groups of
patients with PD were studied: 1) Patients with the spo-
radic form of PD at different stages of the disease (193
persons); 2) Newly diagnosed untreated patients with the
sporadic form of PD (Hoehn and Yahr scores 1 - 2) (48
persons). In total, we recruited 241 sporadic patients with
PD (115 males, 126 females). The mean age ± SD at dis-
ease onset was 47.4 ± 13.6 years (30 - 74), and the mean
age at enrollment was 56.5 ± 13.8 years (32 - 83). Two
hundred twenty-six neurologically normal age-matched
individuals from the same population were studied as
controls. All blood samples were collected with the in-
formed consent of the investigated persons. The study
was approved by the Ethics Committee of the Research
Center of Neurology, RAMS.
2.2. Genetic Analysis
Isolation of genomic DNA from leukocytes was per-
formed using the AxyPrepBlood Genomic DNA Mini-
prep Kit (Axygen, Tewksbury, MA, USA) according to
the manufacturer’s recommendations.
To determine the genotypes of SNPs rs2583988,
rs2619363, rs2619364 and rs2736990 in the SNCA gene,
real-time TaqMan® PCR assays (ID: C_16258278_10,
C_16036895_10, C_3113461_10 and C_3208948_10,
respectively) were used (Applied Biosystems, Foster City,
CA, USA). The real-time PCR and thermal cycling were
performed according to the manufacturer’s instructions
using StepOnePlus (Applied Biosystems). Each blood
sample was analyzed in three independent runs for cor-
rections of differences in sample quality.
2.3. Expression Analysis
For expression analysis, all blood samples were taken at
8:00 a.m. before eating and then stored for less than 2 h
at +4˚C before isolation of RNA. Isolation of total RNA
from whole blood was performed using the ZR Whole-
Blood Total RNA Kit™ (Zymo Research Corp., Irvine,
CA, USA) according to the manufacturer’s recommenda-
tions. Reverse transcription was carried out using the
RevertAid™ H Minus Reverse Transcriptase kit (Fer-
mentas, Vilnius, Lithuania).
Relative levels of the expression of SNCA gene and
reference genes (POLR2F, PSMB6 and PSMA5) were
analyzed using TaqMan real-time PCR. Transcripts of
reference genes were amplified together with the SNCA
transcript to normalize gene expression data. Primers and
probes were designed using Beacon Designer 7.02 soft-
ware (Table 1).
Real-time reactions were conducted using the ANK-32
machine (Institute for Analytical Instrumentation, St.
Petersburg, Russia) and PCR reagents (Syntol, Moscow,
Russia). Thermal cycling was performed as follows: 1)
600 s at 95˚C and 2) 45 cycles of 50 s at 95˚C and 20 s at
60˚C.
It is necessary to note that each blood sample was ana-
lyzed in three independent runs for corrections of differ-
ences in sample quality and reverse transcription effi-
ciency. Normalization was performed on the basis on
amplification levels of reference genes. To assess the
relative levels of gene expression, the method of com-
parison of amplification thresholds ΔCt was used [26].
2.4. Statistical Analysis
Estimation of OR and statistical significance of differ-
ences in allele and genotype distribution were performed
using the software GraphPad InStat v 3.06 (GraphPad
Software, Inc.).
The Hardy-Weinberg equilibrium calculator was used
to calculate the compliance of genotype distribution in a
opulation to the Hardy-Weinberg equilibrium using the p
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Polymorphisms in the SNCA Gene: Association with the Risk of Development of the Sporadic Form of
Parkinson’s Disease and the Level of SNCA Gene Expression in Peripheral Blood of Patients from Russia
Open Access NM
210
Table 1. Primers and probes used in the expression analysis.
Gene Nucleotide sequences
SNCA
[GenBank: BC108275]
P: 5’-ROX-TGTTCTCTATGTAGGCTCCAA-RTQ2-3’
F: 5’-AGCAGGAAAGACAAAAGAGG-3’
R: 5’-TTGCTCTTTGGTCTTCTCAG-3’
POLR2F
[GenBank: DA372532.1]
P: 5’-FAM-CTTCATCCTCCTCCACATCATCAAAGTCGTCG-RTQ1-3’
F: 5’-ATGTCAGACAACGAGGACAATTTTG-3’
R: 5’-TCTTCGGCATTCTCCAAGTCATC-3’
PSMB6
[GenBank: BC000835]
P: 5’-FAM-AGCCGAGAAGTTTCCACTGGGACCACTATC-RTQ1-3’
F: 5’-CGGAGGCGTTCACTCCAG-3’
R: 5’-TCGATTGGCGATGTAGGACC-3’
PSMA5
[GenBank: AK304448.1]
P: 5’-AGCCATCAAGTCTTCACTCATCATCCTC-RTQ1-3’
F: 5’-AGAAGTTTACCACAAGTCTATGAC-3’
R: 5’-CATTCAGCTTCTCCTCCATTAC-3’
P—probe, F—forward primer, R—reverse primer.
χ2 method [27].
Analysis of the expression levels and the calculation of
the median ΔCt were performed using the software MS
Excel 2010 (Microsoft).
Significance of the differences in expression levels of
different genotypes was determined by the Kruskal-
Wallis ANOVA method using the software package Sta-
tistica for Windows 8.0 (StatSoft, Inc. 2007).
3. Results
3.1. Genetic Analysis
In this study, we analyzed four SNPs, three of which
were located in the promoter region of the SNCA gene
(rs2619363, rs2619364 and rs2583988); SNP rs2736990
was located in the fourth intron of the same gene. For
each studied SNP, the genotype distribution is consistent
with the Hardy–Weinberg equilibrium (for rs2583988: χ2
= 0.23 and p = 0.63; for rs2619363: χ2 = 0.01 and p =
0.92; for rs2619364: χ2 = 0.08 and p = 0.77; for
rs2736990: χ2 = 1.32 and p = 0.25). Genotype data are
shown in Table 2.
The presented data show no statistically significant
differences in the genotype distribution of the three SNPs
(rs2583988, rs2619363 and rs2619364), located in the
SNCA promoter region, between patients with PD and the
population control. However, a statistically significant
difference was shown in the genotype distribution of
rs2736990 between the studied groups. Genotype CC
predominates in patients with PD and the presence of the
C allele is associated with an increased risk of the devel-
opment of PD.
3.2. Analysis of mRNA Levels of SNCA
Transcripts
We investigated whether the relative mRNA levels of the
SNCA gene depend on the genotypes of rs2583988,
rs2619363, rs2619364 and rs2736990 in patients with PD
with early stages of the disorder. The results are summa-
rized in Table 3.
Carriers of the rare TT genotype (rs2583988 and
rs2619363) and GG genotype (rs2619364) have higher
relative mRNA levels of SNCA gene compared with
more common genotypes of these SNPs (Table 3) in
patients with PD. On the other hand, it was found that the
TT genotype of rs2736990 is associated with lower rela-
tive expression levels of SNCA mRNA than genotypes
CC and CT. However, the observed differences are not
statistically significant.
It should be noted that the data on the relative expres-
sion levels for rs2583988 and rs2619364 coincide. Such
coincidence is observed in genotype frequencies of these
polymorphisms (Table 2). Perhaps this is because these
two SNPs are in complete linkage disequilibrium.
4. Discussion
We carried out a genotype analysis of rs2736990, for
which an association with the development of PD, has
been repeatedly shown. Our findings are consistent with
the GWAS observations [13,28,29]. As can be seen from
Table 2, we succeeded in showing an association of
rs2736990 in the SNCA gene with the risk of the sporadic
form of PD in the Russian population.
We obtained OR = 1.9 (95% CI: 1.24 - 2.91, p =
0.003), which reflects an increased risk of PD almost
twofold in carriers of allele C. These findings are also
supported by results of genome-wide studies by Simón-
Sánchez and Edwards (OR = 1.29 at p = 0.01, OR = 1.27
at p = 6.17 × 10 - 13 and OR = 1.23 and p = 2.24 × 10 -
16), obtained in large groups of patients with PD [12,
30,31]. Furthermore, during analysis of the expression
levels of SNCA transcripts, it was shown that these levels
were higher in carriers with genotypes CC and CT in
rs2736990 than that in patients carrying the TT genotype,

Polymorphisms in the SNCA Gene: Association with the Risk of Development of the Sporadic Form of
Parkinson’s Disease and the Level of SNCA Gene Expression in Peripheral Blood of Patients from Russia
211
Table 2. Allelic and genotype freque nc ie s of SNPs in SNCA.
Alleles N (%) Genotypes N (%) Odds Ratio (95%
confidence interval, CI)р
rs2583988 C T CC CT TT (CC + CT)/TT
Patients with sporadic form of PD (241) 219 (0.66) 115 (0.34)126 (0.52)93 (0.39)22 (0.09)
Population control (226) 207 (0.66) 107 (0.34)119 (0.52)88 (0.40)19 (0.08)0.91 (0.48 - 1.74) 0.87
rs2619363 G T GG GT TT (GG+GT)/TT
Patients with sporadic form of PD (238) 218 (0.66) 114 (0.34)124 (0.52)94 (0.40)20 (0.08)
Population control (226) 209 (0.66) 108 (0.34)118 (0.52)91 (0.40)17 (0.08)0.88 (0.45 - 1.74) 0.73
rs2619364 A G AA AG GG (AA + AG)/GG
Patients with sporadic form of PD (240) 218 (0.66) 115 (0.34)125 (0.52)93 (0.39)22 (0.09)
Population control (226) 207 (0.66) 109 (0.34)117 (0.52)90 (0.40)19 (0.08)0.91 (0.48 - 1.73) 0.87
rs2736990 C T CC CT TT (CC + CT)/TT
Patients with sporadic form of PD (228) 181 (0.57) 136 (0.43)92 (0.40) 89 (0.39)47 (0.21)
Population control (224) 150 (0.46) 176 (0.54)48 (0.21) 102 (0.46)74 (0.33)1.9 (1.24 - 2.91) 0.003
Table 3. Relative mRNA levels of SNCA transcripts and tested SNP s ge notypes in patients with PD.
SNP Genotypes p
rs2583988 СС СT TT
Relative expression mRNA level
of SNCA
−5.97
(−8.01 - −2.77)
−5.58
(−6.80 - −3.44)
−5.34
(−6.28 - −4.33) 0.74
rs2619363 GG GT TT
Relative expression mRNA level
of SNCA
−5.80
(−8.01 - −2.77)
−5.57
(−6.80 - −2.91)
−5.65
(−6.87 - −4.33) 0.75
rs2619364 AA AG GG
Relative expression mRNA level
of SNCA
−5.97
(−8.01 - −2.77)
−5.58
(−6.80 - −3.44)
−5.34
(−6.28 - −4.33) 0.74
rs2736990 CC CT TT
Relative expression mRNA level
of SNCA
−5.40
(−6.28 - −2.92)
−5.86
(−7.73 - −2.77)
−7.18
(−8.92 - −5.05) 0.23
although the differences were not statistically significant.
As mentioned above, rs2736990 is located in the center
of the fourth intron of the SNCA gene. Studies of patients
with PD from Germany and Japan demonstrated that
there was a linkage between intron 4 and the 5’- and 3’-
untranslated regions (UTRs) of SNCA [32,33]. Perhaps
rs2736990 is linked with the functionally significant
variant in the 3’ or 5’ UTRs of the gene that may influ-
ence the expression of SNCA.
Rs2583988, rs2619363 and rs2619364, located in the
SNCA gene and linked with Rep1, were also genotyped
in this study [20,21]. Our study showed no association of
these SNPs and the development of PD in Russian pa-
tients (OR = 0.88 - 0.91, 95% CI: 0.45 - 1.74, p = 0.73 -
0.87). These data are consistent with the investigation of
Irish patients with PD, where no association among
rs2583988, rs2619363 and rs2619364 and the develop-
ment of PD was found (OR = 1.14 - 1.18, 95% CI: 0.76 -
1.78) [19]. However, higher relative levels of SNCA
mRNA were observed in PD patients carrying the TT
genotype (for rs2583988 and rs2619363) and the GG
genotype (for rs2619364) in peripheral blood compared
with carriers of the C allele in rs2583988, G—in
rs2619363 and A—in rs2619364. Although no associa-
tion of any change in the expression levels of the SNCA
gene with SNPs rs2583988 and rs2619363 was found in
the work by Linnertz, at the same time, an association
between changes in SNCA gene expression and Rep1,
linked with these polymorphisms, was demonstrated [18].
It seems like that the three SNPs in the promoter region
of the SNCA gene have an insignificant effect on the ex-
pression of SNCA.
It is possible that rs2736990 or/and an unknown linked
causal sequence variant may regulate transcription of
SNCA either directly or indirectly through coordination
with transcriptional enhancers and repressors. The results
of our study improved our understanding of the contribu-
tion of genetic variants within the SNCA locus to spo-
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Polymorphisms in the SNCA Gene: Association with the Risk of Development of the Sporadic Form of
Parkinson’s Disease and the Level of SNCA Gene Expression in Peripheral Blood of Patients from Russia
212
radic PD. Better knowledge of the molecular mecha-
nisms that modulate SNCA gene expression, may lead to
novel therapeutic approaches based on changes in SNCA
levels. Further, this SNP rs2736990 in SNCA gene may
be included into the panel of biomarkers for the assess-
ment of the individual risk of PD development.
5. Acknowledgements
This work was supported by the Russian Foundation for
Basic Research (projects no. 12-04-31091, 12-04-01183-
а), as well as by programs of the Russian Academy of
Sciences (Molecular and Cellular Biology, Fundamental
Sciences for Medicine), state contracts (no. 16.740.11.
0630, 8605, 8851, 14.512.11.0043 and 14.122.13.641-
MK).
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Polymorphisms in the SNCA Gene: Association with the Risk of Development of the Sporadic Form of
Parkinson’s Disease and the Level of SNCA Gene Expression in Peripheral Blood of Patients from Russia
Open Access NM
214
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List of the Abbreviations
PD—Parkinson’s disease,
SNP— single-nucleotide polymorphism,
GWAS—genome—wide associated study,
OR—odds ratio,
CI—confidence interval,
UTR—untranslated region.