Association of LAG3 genetic variation with an increased risk of PD in Chinese female population

Wenyuan Guo,Pingyi Xu,Yuwan Lin,Shuxuan Huang,Xiang Chen,Jiewen Qiu,Xiaoqin Zhu,Guoyou Peng,Miaomiao Zhou,Hanqun Liu,Mingshu Mo

doi:10.1186/s12974-019-1654-6

Abstract

BackgroundEmerging evidence suggests that α-synuclein (α-syn) aggregation and intercellular transmission contributes to pathogenesis of Parkinson’s disease (PD) and the toxic fibrillary α-syn binds lymphocyte-activation gene 3 (LAG3) receptor that mediates α-syn transmission. The deletion of LAG3 in animal models was shown to limit α-syn spreading and alleviate the pathological changes of dopaminergic neurons and animal behavioral deficits induced by α-syn aggregation. However, little is known about the genetic association of LAG3 variation with human PD development.ObjectiveHere we investigated LAG3 single nucleotide polymorphisms (SNPs) and examined the levels of soluble LAG3 (sLAG3) of CSF and serum from Chinese PD patients.MethodsWe enrolled 646 PD patients and 536 healthy controls to conduct a case-control study. All the participants were genotyped using Sequenom iPLEX Assay and the partial cerebrospinal fluid (CSF) and serum samples were assessed by Meso Scale Discovery electrochemiluminescence (MSD-ECL) immunoassay to measure sLAG3 concentration.ResultsAs a result, distributions of rs1922452-AA (1.975, 95% confidence interval (CI) 1.311–2.888, p = 0.001) and rs951818-CC (OR = 2.03, 95% CI 1.369–3.010, p = 0.001) genotype frequencies were found higher in the female PD patients than controls, respectively, and a strong linkage disequilibrium (LD) was calculated on the variants. The level of sLAG3 in CSF of PD patients was found to significantly differ from that of controls (51.56 ± 15.05 pg/ml vs 88.49 ± 62.96 pg/ml, p < 0.0001). Meanwhile, the concentration of α-synuclein in CSF of patients was significantly lower than that of controls (939.9 ± 2900 pg/ml vs 2476 ± 4403 pg/ml, p < 0.0001) and the level of sLAG3 was detected to be positive correlation with that of α-synuclein in the control group (r = 0.597, p = 0.0042), but not in PD group (r = 0.111, p = 0.408).ConclusionIn summary, our data suggested that LAG3 SNPs increase the PD risk of Chinese female population and the sLAG3 may be a potential biomarker predicted for PD development.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disease that affects 1% of individuals aged > 60 in the world [1]
As a result, distributions of rs1922452-AA (1.975, 95% confidence interval (CI) 1.311–2.888, p = 0.001) and rs951818-CC (OR = 2.03, 95% CI 1.369–3.010, p = 0.001) genotype frequencies were found higher in the female PD patients than controls, respectively, and a strong linkage disequilibrium (LD) was calculated on the variants
In summary, our data suggested that lymphocyte-activation gene 3 (LAG3) Single nucleotide polymorphisms (SNPs) increase the PD risk of Chinese female population and the soluble LAG3 (sLAG3) may be a potential biomarker predicted for PD development

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease that affects 1% of individuals aged > 60 in the world [1]. Recent studies indicated that immune dysfunction is required for the progression of PD initiated by αsynuclein aggregation [8]. This extracellular α-syn can activate microglia to initiating an inflammatory response. Α-syn fragments could be identified and presented to T cells to induce toxic T cell response in the peripheral blood cells of PD patients, which has a similar feature with autoimmune disease [12]. Emerging evidence suggests that α-synuclein (α-syn) aggregation and intercellular transmission contributes to pathogenesis of Parkinson’s disease (PD) and the toxic fibrillary α-syn binds lymphocyte-activation gene 3 (LAG3) receptor that mediates α-syn transmission. Little is known about the genetic association of LAG3 variation with human PD development

Methods

Results

Discussion

Conclusion