Short communicationSTX6 rs1411478 is not associated with increased risk of Parkinson's disease
Introduction
Parkinson's disease (PD) is a progressive neurodegenerative condition characterized by resting tremor, bradykinesia, rigidity and postural instability. PD affects more than 1% of the population at age 65 and increases to 4–5% at age 85 [1]. PD is the most common cause of degenerative parkinsonism, followed by progressive supranuclear palsy (PSP). PSP is characterized by falls, axial rigidity, vertical supranuclear gaze palsy, bradykinesia and cognitive decline [2]. Diagnosis of PSP may be challenging at early disease stages and can be misdiagnosed for PD because their initial clinical features may be similar, although the symptoms in PSP progress much faster [2]. In addition to the clinical resemblances between PSP and PD, there is also evidence of a genetic overlap between these two diseases. Although the specific haplotype associated with disease is slightly different [3], [4], genome wide association studies of PD and PSP have found the H1 haplotype of MAPT consistently associated with increased risk of disease in Caucasian populations [5], [6] suggesting a common molecular pathway for both diseases.
A variant in Syntaxin 6 (STX6) was identified as a risk factor for PSP [5]. STX6 encodes syntaxin 6, a soluble N-ethylmaleimide-sensitive factor attachment protein receptor SNARE-class protein, localized to the trans-Golgi network and endosomal structures and important in the fusion of vesicles with membranes [7]. SNARE-complex assembly is required for the repeated release of neurotransmitters. Vesicle dynamics has already been implicated in PD through α-synuclein biology. Although much of the normal function of α-synuclein has yet to be elucidated, it is known to directly bind to VAMP2 (vesicle-associated membrance protein 2) in SNARE complexes to promote presynaptic complex assembly [8]. Knockout mice that lacked α, β and γ synucleins present a reduction in size of presynaptic terminals, increased axonal width and decreased conduction velocity, retinal degeneration and decreased survival [8]. Additional support for a role for vesicular sorting and trafficking of membrane-associated proteins in PD biology has been provided by pathogenic mutations in LRRK2 [9], VPS35 resulting in autosomal dominant PD [10], and DNAJC6 mutations causing juvenile recessive PD [11].
Hoglinger et al., 2011 found three single nucleotide polymorphisms (SNPs) that were significantly associated with PSP risk at STX6, EIF2AK3 and MOBP. STX6 rs1411478 has an odds ratio of 0.73 (range from 0.65 to 0.81) and a p-value of 1.8 × 10−9. Given the functional role of STX6 and the overlap between PD and PSP, we set out to evaluate whether the PSP risk variant identified in STX6 may be relevant to the molecular etiology of PD. To this end, we evaluated the presence of pathogenic mutations in probands and assessed the risk for SNP rs1411478 in PD case–control series from Canada, Norway, Taiwan and Tunisia.
Section snippets
Materials and methods
Genotyping of rs1411478 was performed in 1503 patients with PD and 1350 controls from Canada, Norway, Taiwan and Tunisia. All subjects provided written informed consent before their participation in the study. Ethical approvals were obtained from local Ethical Committees. All protocols and procedures have been independently reviewed by the University of British Columbia Research Ethics Board. The series with PD was comprised of both familial and sporadic cases. Sample descriptives are provided
Results
The genotype frequencies and statistical analysis for STX6 rs1411478 are given in Table 1. Samples from each population were in Hardy–Weinberg equilibrium. Statistical analysis did not show a difference in STX6 rs1411478 allelic frequencies or genotypic distributions between patients with PD and control subjects, between countries or combined.
Sequencing STX6 in 67 familial probands identified three previously reported synonymous changes: p.E13E (rs12125196), p.Q1221Q (rs34036241) and p.N217N
Discussion
The clinical and genetic overlap between PD and PSP suggests a common physiological mechanism may be implicated in both diseases. Allelic variability in STX6 was recently associated with PSP (odds ratio 0.79 (95% CI 0.74–0.85)) [5]. We evaluated the role of STX6 rs1411478 in patients with PD and control subjects from Canada, Norway, Taiwan and Tunisia. Our analysis did not identify statistical differences in allele frequency or genotype distributions within the populations studied,
Acknowledgments
We are grateful to all individuals who generously participated in this study. This research was undertaken, in part, thanks to funding from the Canada Excellence Research Chairs program (MJF), Leading Edge Endowment Funds provided by the Province of British Columbia, LifeLabs, and Genome BC support the Dr. Donald Rix BC Leadership Chair (MJF), and the Cundhill Foundation (MJF). The authors wish to thank Dr. Rachel Gibson and the GlaxoSmithKline PD Program Team.
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