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

Abstract

Parkinson's disease (PD) is one of the most common human neurodegenerative disorders caused by the loss of dopaminergic neurons in the brain. The α-synuclein (SNCA) gene is one of the most studied genes involved in the pathogenesis 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.

Variants in SNCA Gene Are Associated with Parkinson’s Disease Risk and Cognitive Symptoms in a Brazilian Sample

“…Human studies demonstrated reduction of SNCA-mRNA levels in brain tissues and protein levels in blood in the absence of REP1 risk allele ( Fuchs et al, 2008 ; Linnertz et al, 2009 ). Despite some evidence of correlations between rs2583988 and REP1 variants ( Pals et al, 2004 ; Winkler et al, 2007 ; Myhre et al, 2008 ), no significant associations of rs2583988 were found for assessment of blood protein levels ( Fuchs et al, 2008 ) or SNCA-mRNA ( Fuchs et al, 2008 ; Linnertz et al, 2009 ; Alieva et al, 2013 ).…”

“…Two major linkage disequilibrium blocks in SNCA gene had been proposed ( Mueller et al, 2005 ; Myhre et al, 2008 ): a 5′ block that extends to promoter-enhancer region to exon 4 and a 3′ block that comprises intron, 3′ untranslated region, and the 3′ end region of the gene. Associations between SNPs rs2583988 in 5′ region ( Pals et al, 2004 ; Winkler et al, 2007 ; Heckman et al, 2012 ; Trotta et al, 2012 ), rs2736990 in intron 4 ( Mata et al, 2011 ; Heckman et al, 2012 ; Miyake et al, 2012 ; Alieva et al, 2013 ; Guo et al, 2014 ; Davila-Ortiz de Montellano et al, 2016 ), rs356219 ( Lazzarini et al, 1994 ; Mata et al, 2010 , 2011 ; Botta-Orfila et al, 2011 ; Wider et al, 2011 ; Trotta et al, 2012 ; Brockmann et al, 2013 ; Emelyanov et al, 2013 ), and rs11931074 ( Gao et al, 2012 ; Wu-Chou et al, 2013 ) in 3′ end were demonstrated by recent studies. A meta-analysis confirmed the risk association of rs2583988, rs356219, and rs11931074 variants and PD susceptibility, performed in dominant and recessive genetic models ( Han et al, 2015 ).…”

“…Studies have investigated the functional effects of the different SNCA SNPs on gene expression in brain tissues and protein levels in blood samples, but the results were inconsistent ( Fuchs et al, 2008 ; Linnertz et al, 2009 ; Mccarthy et al, 2011 ; Alieva et al, 2013 ; Cardo et al, 2014 ). For example, a study with a transgenic mouse model demonstrated that REP1 variants in 5′ region affect the regulation of transcriptional activity ( Cronin et al, 2009 ).…”

“…For the intronic SNP rs2736990, an investigation of gene expression revealed a trend toward lower levels of SNCA-mRNA in blood samples of PD patients ( Alieva et al, 2013 ), but in healthy subjects the T allele was correlated with higher levels of the isoform SNCA112-mRNA in frontal cortex tissue samples.…”