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Alpha-synuclein repeat variants and survival in Parkinson's disease.

ABSTRACT: To determine whether ?-synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD).Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium provided REP1 genotypes and baseline and follow-up clinical data for cases. The primary outcome was time to death. Cox proportional hazards regression models were used to assess the association of REP1 genotypes with survival.Twenty-one sites contributed data for 6,154 cases. There was no significant association between ?-synuclein REP1 genotypes and survival in PD. However, there was a significant association between REP1 genotypes and age at onset of PD (hazard ratio: 1.06; 95% confidence interval: 1.01-1.10; P value?=?0.01).In our large consortium study, ?-synuclein REP1 genotypes were not associated with survival in PD. Further studies of ?-synuclein's role in disease progression and long-term outcomes are needed.

SUBMITTER: Chung SJ

PROVIDER: S-EPMC4172351 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Alpha-synuclein repeat variants and survival in Parkinson's disease.

Chung Sun Ju SJ Biernacka Joanna M JM Armasu Sebastian M SM Anderson Kari K Frigerio Roberta R Aasly Jan O JO Annesi Grazia G Bentivoglio Anna Rita AR Brighina Laura L Chartier-Harlin Marie-Christine MC Goldwurm Stefano S Hadjigeorgiou Georgios G Jasinska-Myga Barbara B Jeon Beom Seok BS Kim Yun Joong YJ Krüger Rejko R Lesage Suzanne S Markopoulou Katerina K Mellick George G Morrison Karen E KE Puschmann Andreas A Tan Eng-King EK Crosiers David D Theuns Jessie J Van Broeckhoven Christine C Wirdefeldt Karin K Wszolek Zbigniew K ZK Elbaz Alexis A Maraganore Demetrius M DM

Movement disorders : official journal of the Movement Disorder Society 20140227 8

<h4>Objectives</h4>To determine whether α-synuclein dinucleotide repeat (REP1) genotypes are associated with survival in Parkinson's disease (PD).<h4>Methods</h4>Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium provided REP1 genotypes and baseline and follow-up clinical data for cases. The primary outcome was time to death. Cox proportional hazards regression models were used to assess the association of REP1 genotypes with survival.<h4>Results</h4>Twenty-one sites c ...[more]

PMID: 24578302

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Project description:Importance. Biological markers of Parkinson’s disease are essential for achieving disease modification. Objective. To determine the association of SNCA blood transcript levels with prevalence of Parkinson’s disease. Background. The SNCA locus is preferentially transcribed in neurons and blood cells. Non-coding genetic variants and neuronal aggregates of α-synuclein protein associate this locus with sporadic Parkinson’s disease and suggest a potential role for abnormal SNCA transcription in the disease mechanism. Here we investigated variation in intracellular SNCA gene expression and SNCA transcript isoform abundance in circulating blood cells of cases with PD and controls in a network of biobanks that represent regional, national, and international populations. Design, Setting, Participants. Three cross-sectional, case-control studies nested in observational biomarker studies. 222 cases with early-stage clinical PD and 183 controls were enrolled from 2005 to 2010 in the Harvard Biomarker Study (HBS) at two Harvard-affiliated tertiary care centers. 76 cases with dopamine transporter imaging (DAT)-confirmed PD and 42 controls were enrolled between August 2007 and December 2008 in the Blood α-Synuclein, Gene Expression and Smell Testing as Diagnostic and Prognostic Biomarkers in Parkinson’s Disease Study (PROBE) study from 22 US tertiary care centers. 202 DAT-confirmed cases with de novo PD and 138 controls were enrolled in the Parkinson’s Progression Markers Initiative (PPMI) between July 2010 and November 2012 from 22 US and international tertiary care centers. Main Outcome Measures. Association of intracellular SNCA transcript abundance with PD estimated on analog and digital expression platforms. Results. Reduced levels of SNCA transcripts were associated with early-stage clinical PD, neuroimaging-confirmed PD, and untreated, neuroimaging-confirmed PD in accessible, peripheral blood cells from a total of 863 individuals. SNCA expression was reduced by 17%, 22%, and 16% in cases compared to controls in the HBS, PROBE, and PPMI study with P values of 0.004, 0.025, and 0.018, respectively, after adjusting for clinical, hematological, and processing covariates. Specific SNCA transcripts with long 3’ untranslated regions (UTR) and those skipping exon 5 are implicated in the accumulation and mitochondrial targeting of α-synuclein protein in Parkinson’s pathology. These transcript isoforms were linked to PD through digital expression analysis. Individuals in the lowest quartile of SNCA expression values had covariate-adjusted odds ratios for PD of 2.14 (95% C. I. 1.1-4.1), 4.5 (95% C. I. 1.3-15), and 2.1 (1.1-4.0) compared to individuals in the highest quartile of expression values in the HBS, PROBE, and PPMI study, respectively. Conclusions and Relevance. Reduced levels of SNCA expression, particularly of disease-relevant transcripts with extended 3’ UTR or exon 5 skipping, are associated with early-stage PD. These findings support a potential role for SNCA as a transcriptional marker of PD and may have implications for patient stratification and risk assessment.

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Alpha-synuclein repeat variants and survival in Parkinson's disease.

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Alpha-synuclein repeat variants and survival in Parkinson's disease.

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