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SNCA variant associated with Parkinson disease and plasma alpha-synuclein level.

ABSTRACT: A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson disease (PD). There is also increasing evidence that single-nucleotide polymorphisms (SNPs) elsewhere in the gene are associated with PD risk.To further explore the association of common SNCA SNPs with PD susceptibility, to determine whether evidence of allelic heterogeneity exists, and to examine the correlation between PD-associated variants and plasma ?-synuclein levels.Two-tiered analysis.Academic research.Patients and control subjects from the NeuroGenetics Research Consortium.We performed a 2-tiered analysis of 1956 patients with PD and 2112 controls from the NeuroGenetics Research Consortium using a comprehensive tag SNP approach. Previously published REP1 genotypes were also included. Plasma ?-synuclein was assayed in 86 patients with PD and 78 controls using a highly sensitive Luminex assay.Five of 15 SNPs genotyped were associated with PD under an additive model in tier 1 (? = .05). Of these, 4 were successfully replicated in tier 2. In the combined sample, the most significant marker was rs356219 (odds ratio, 1.41; 95% confidence interval, 1.28-1.55; P = 1.6 × 10(-12)), located approximately 9 kilobases downstream from the gene. A regression model containing rs356219 alone best fit the data. The linkage disequilibrium correlation coefficient between this SNP and REP1 was low (r(2) = 0.09). The risk-associated C allele of rs356219 was also correlated with higher transformed plasma ?-synuclein levels in patients under an adjusted additive model (P = .005).Our data suggest that 1 or more unidentified functional SNCA variants modify risk for PD and that the effect is larger than and independent of REP1. This variant(s), tagged by rs356219, might act by upregulating SNCA expression in a dose-dependent manner.

SUBMITTER: Mata IF

PROVIDER: S-EPMC3010848 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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SNCA variant associated with Parkinson disease and plasma alpha-synuclein level.

Mata Ignacio F IF Shi Min M Agarwal Pinky P Chung Kathryn A KA Edwards Karen L KL Factor Stewart A SA Galasko Douglas R DR Ginghina Carmen C Griffith Alida A Higgins Donald S DS Kay Denise M DM Kim Hojoong H Leverenz James B JB Quinn Joseph F JF Roberts John W JW Samii Ali A Snapinn Katherine W KW Tsuang Debby W DW Yearout Dora D Zhang Jing J Payami Haydeh H Zabetian Cyrus P CP

Archives of neurology 20101101 11

<h4>Background</h4>A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson disease (PD). There is also increasing evidence that single-nucleotide polymorphisms (SNPs) elsewhere in the gene are associated with PD risk.<h4>Objectives</h4>To further explore the association of common SNCA SNPs with PD susceptibility, to determine whether evidence of allelic heterogeneity exists, and to examine the correlation between PD-associated variants and plasma α-synuc ...[more]

PMID: 21060011

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Project description:The most established pathognomonic protein of Parkinson's disease (PD), α-synuclein, is extensively investigated for disease diagnosis and prognosis; however, investigations into whether the free form of α-synuclein in the blood functions as a PD biomarker have not been fruitful. Extracellular vesicles (EVs) secreted from cells and present in blood transport molecules are novel platforms for biomarker identification. In blood EVs, α-synuclein originates predominantly from the brain without the interference of the blood-brain barrier. The present study investigated the role of plasma EV-borne α-synuclein as a biomarker of PD. Patients with mild to moderate stages of PD (n = 116) and individuals without PD (n = 46) were recruited to serve as the PD study group and the control group, respectively. Plasma EVs were isolated, and immunomagnetic reduction-based immunoassay was used to assess EV α-synuclein levels. Conventional statistical analysis was performed using SPSS 25.0, and p < 0.05 was considered significant. Compared with controls, we observed significantly lower plasma EV α-synuclein levels in the patients with PD (PD: 56.0 ± 3.7 fg/mL vs. control: 74.5 ± 4.3 fg/mL, p = 0.009), and the significance remained after adjustment for age and sex. Plasma EV α-synuclein levels in the patients with PD did not correlate with age, disease duration, Part I and II scores of the Unified Parkinson's Disease Rating Scale (UPDRS), or the Mini-Mental State Examination scores. However, such levels were significantly correlated with UPDRS Part III score, which assesses motor dysfunction. Furthermore, the severity of akinetic-rigidity symptoms, but not tremor, was inversely associated with plasma EV α-synuclein level. Plasma EV α-synuclein was significantly different between the control and PD group and was associated with akinetic-rigidity symptom severity in patients with PD. This study corroborates the possible diagnostic and subtyping roles of plasma EV α-synuclein in patients with PD, and it further provides a basis for this protein's clinical relevance and feasibility as a PD biomarker.

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SNCA variant associated with Parkinson disease and plasma alpha-synuclein level.

Publications

SNCA variant associated with Parkinson disease and plasma alpha-synuclein level.

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