Variants in the SNCA Locus Are Associated With the Progression of Parkinson's Disease

Abstract

Background: Genetic factors have a well-known influence on Parkinson's disease (PD) susceptibility; however, no previous studies have investigated the influence of SNCA mutations on the natural history of PD using a prospective follow-up study. The aim of this study was to assess the risk factors of variation of SNCA on the prognosis symptoms of PD patients. Methods: Fifty PD patients were recruited with 38 v-PSG confirmed PD+RBD patients, and the median follow-up period was 30 months. All patients underwent a comprehensive clinical evaluation at baseline and follow-up, and six SNPs of SNCA (rs356165, rs3857053, rs1045722, rs894278, rs356186, and rs356219) were analyzed. Cox proportional hazards regression models and Kaplan–Meier plot analysis were used to assess the associations between the SNCA variation and the primary and secondary progression outcomes. Results: Based on the clinical assessment, we found that hyposmia was substantially easier to aggravate. Regression analysis showed that patients with the T allele of rs1045722 and the G allele of rs356219 presented a 34 and 20% decreased risk of progression to the H-Y stage, respectively ( p = 0.022; p = 0.005). While for rs894278, G allele patients showed a 47% decreased risk of olfactory dysfunction ( p = 0.029). Further subgroup analysis showed that PD+RBD patients with rs356219/G exhibited a 30% and 20% decreased risk of progression on the H-Y stage and MoCA score ( p = 0.038; p = 0.045). Conclusions: Our results indicated that genetic variation in SNCA may contribute to variability natural progression of PD and could possibly be used as a prognostic marker.

Association of SNCA Parkinson's Disease Risk Polymorphisms With Disease Progression in Newly Diagnosed Patients

“…No differences between genotype groups and the annual change in MMSE score were observed for the control subjects over the same follow-up period, indicating that this effect is disease-specific. Similar to our findings, Luo et al ( 21 ) found an association between the rate of cognitive impairment and rs356219. However, in their study of patients with PD from China, carriers of the G-allele had a decreased risk of cognitive decline, indicating that the G allele might have a protective role in this population ( 21 ).…”

“…Similar to our findings, Luo et al ( 21 ) found an association between the rate of cognitive impairment and rs356219. However, in their study of patients with PD from China, carriers of the G-allele had a decreased risk of cognitive decline, indicating that the G allele might have a protective role in this population ( 21 ). In an analysis of European patients with PD, Goris et al reported no association of rs356219 with the annual change in MMSE ( 22 ).…”

A systematic review of associations between common SNCA variants and clinical heterogeneity in Parkinson’s disease

“…Fourteen studies including a total of 31 different polymorphisms used the H&Y scale to measure PD severity (Supplementary Table 3 ), but the means by which the scale was used varied widely. For example, Davis et al report no significant association between rs356219 or rs11931074 and the annual change in H&Y stage 22 , while in other studies these same SNPs were shown to be significantly associated with either a longer time to a 0.5-point increase in H&Y stage (rs356219; HR 0.20; p = 0.005) 37 or a longer time to reach H&Y stage ≥3 (mild-to-moderate disability) (rs11931074; HR 0.43; p = 0.03) 31 . Similarly, REP1 score was reported to be associated with a longer time to reach H&Y stage ≥4 (severe disability) (HR 0.87; p = 0.046) 38 , while reports on the association of the REP1 polymorphism with H&Y stage at the time of examination are conflicting 34 , 36 .…”

“…In the most comprehensive assessment of cognitive performance and rs356219, Mata et al analyzed global cognitive function using the Montreal Cognitive Assessment (MoCA), and memory; attention and executive function; language processing; and visuospatial skills in 1079 patients with PD of European descent and found no significant association between rs356219 and any outcome 40 . Two small studies did show a significant association of rs356219 with global cognitive impairment, with conflicting results: in a Chinese explorative study of 50 patients, the rs356219-G allele was significantly associated with an 18% decreased risk of cognitive decline ( p = 0.006), measured by the time to a 1-point decrease on the MoCA scale 37 . Conversely, a Brazilian study of 105 patients found that both rs356219 heterozygotes (rs356219-GA; OR 4.74; p = 0.021) and homozygotes (rs356219-GG; OR 5.74; p = 0.014) had significantly increased risk of cognitive impairment as defined by an education-corrected Mini-Mental State Examination (MMSE) cut-off 35 .…”

“…Cognitive decline is an important aspect of PD as it brings a substantial additional burden for the patient, caregivers, and the healthcare system. In 8 of the 21 studies that assessed the association between 36 SNCA polymorphisms and cognition, 4 SNPs 27 , 31 , 35 , 37 , 39 and the REP1 polymorphism 18 , 34 , 38 were shown to be significantly associated with measures of cognitive impairment or the diagnosis of dementia (Fig. 2 and Supplementary Table 3 ).…”