Qiying Sun

Glucocerebrosidase gene L444P mutation is a risk factor for Parkinson's disease in Chinese population.

An association between mutations in the glucocerebrosidase (GBA) gene and Parkinsons disease (PD) has been reported in several populations. We searched for four common GBA mutations (L444P, F213I, R353W, and N370S) in 402 Chinese PD patients and 413 age‐ and sex‐matched controls. In the PD cohort, 11 patients were found carrying a heterozygous GBA mutation and all of them had the L444P mutation. Heterozygous GBA mutations were detected none in controls. The GBA gene L444P mutation was detected at a significantly higher frequency among PD patients (11/402 = 2.74%), when compared with the control group (0/413): P = 0.0007. To evaluate the possible role of the GBA gene L444P mutation in PD in Ashkenazi Jewish and non‐Jewish populations, we conducted a meta‐analysis on the topic. In the Chinese population, the GBA gene L444P mutation was detected at a significantly higher frequency among PD patients, when compared with the control group: Z = 3.83, P = 0.0001, OR = 8.42, confidence interval = 95%, 2.83–25.06. In the non‐Jewish populations, the difference was obviously significant: Z = 5.76, P < 0.00001, OR = 8.82, confidence interval = 95%, 4.21–18.48. The results suggest that the GBA gene L444P mutation appears to be a risk factor for PD in Chinese population.

Screening for two SNPs of LINGO1 gene in patients with essential tremor or sporadic Parkinson's disease in Chinese population

Two markers rs9652490 and rs11856808 both located in intron 3 of the LINGO1 gene have been nominated recently to be associated with essential tremor (ET). Although ET and Parkinsons disease (PD) are considered as different entities, they have many overlapping clinical and pathological features. We aimed to evaluate the role of rs9652490 and rs11856808 in the development of ET and PD. To this point, we sequenced the region involving the two markers in 109 ET cases, 425 sporadic Parkinsons disease (SPD) cases and 430 controls in Chinese population. After stratification by age, the rs9652490G allele suggested protective role in the early onset PD (EOPD, age at onset < or =50 years) group compared with age matched controls (OR=0.56, 95% CI: 0.35-0.90, p=0.015). No other significant association was found. We concluded that the two markers rs9652490 and rs11856808 were not strongly related to the development of ET or late onset SPD, but the rs9652490G allele might be a protective factor for EOPD in Chinese population.

Association Study Between Vitamin D Receptor Gene Polymorphisms and Patients With Parkinson Disease in Chinese Han Population

ABSTRACT Vitamin D and vitamin D receptor (VDR) have been postulated as environmental and genetic factors in neurodegenerative disorders including multiple sclerosis, Alzheimer disease, and recently Parkinson disease (PD). The purpose of this study is to explore the potential correlation between single nucleotide polymorphisms of the VDR gene (VDR) rs4334089 and rs731236 and PD. A total of 483 patients with PD and 498 age- and sex-matched controls were involved in this study. Genotypes were determined by using polymerase chain reaction–restriction fragment length polymorphism and DNA sequencing. There were no significant differences in the genotype and allele frequencies of VDR rs4334089 and rs731236 polymorphisms between the group of patients with PD and the control group in a Chinese Han population (for VDR rs4334089: OR 1.02, 95% CI: 0.85–1.23; for VDR rs731236: OR 1.13, 95% CI: 0.75–1.71). Similarly, there were still no differences when stratifying by age or by gender. These findings suggest that VDR gene is not a susceptibility gene for PD in our population.

PITX3 gene polymorphism is associated with Parkinson's disease in Chinese population

Genetic variants of PITX3 gene have been reported to be associated with Parkinsons disease (PD) in several populations. We conducted a case-control study and genotyped the three SNPs of PITX3 gene: rs2281983, rs4919621 and rs3758549 in 512 mainland Chinese PD patients and 506 healthy controls. Our findings show that the PITX3 gene rs3758549 polymorphism is associated with PD (p=0.02). Moreover, the difference between late onset PD patients and healthy controls is stronger (p=0.007). There is no statistical difference in genotype or allele frequencies of rs2281983 or rs4919621 variant in PITX3 gene between sporadic PD (SPD) group and healthy control group in our study. To assess the possible role of the PITX3 gene rs3758549 polymorphism in PD, we conducted a meta-analysis on the topic. The results of meta-analysis further support that the PITX3 gene rs3758549 polymorphism is associated with PD: Z=3.09, p=0.002, OR=0.89. These findings suggest that the PITX3 gene rs3758549 polymorphism may increase the susceptibility of PD.

VPS35 gene variants are not associated with Parkinson's disease in the mainland Chinese population

In order to determine the prevalence of GIGYF2 (Grb10-Interacting GYF Protein 2) variants in the Chinese population and to better understand the association between GIGYF2 and Parkinsons disease (PD), we conducted the genetic screening of GIGYF2 in the Chinese population. Twelve exonic variants were identified in 52 familial PD probands and 56 healthy controls. Non-synonymous point variants (Thr25Ala, Asn457Th and Pro460Th) were analyzed in 510 PD patients and 481 healthy controls of Chinese Han ethnicity. The insertion and deletion variants in Exon 25 (Ins Q 1212, Ins QQ 1217, Del Q 1210, Del Q 1216 and Del PPQ1217_1219) are not related to the onset of familial PD. Our data indicate the GIGYF2 variants are not associated with PD in the mainland Chinese Population.

Effect of GBA Mutations on Phenotype of Parkinson’s Disease: A Study on Chinese Population and a Meta-Analysis

GBA has been identified as a genetic risk factor for PD. Whether the clinical manifestations of PD patients with or without GBA mutations are different has still not reached a consensus. We firstly detected the GBA mutation L444P in 1147 Chinese PD patients and simultaneously evaluated their corresponding clinical data. Then we compared the phenotypes between 646 PD patients with GBA mutations and 10344 PD patients without GBA mutations worldwide through meta-analysis. Through the method of meta-analysis, there was significant difference in age at onset (MD = −3.10 [95% CI: −4.88, −1.32]), bradykinesia as an initial symptom (OR = 1.49 [95% CI: 1.15, 1.94]), having family history (OR = 1.50 [95% CI: 1.18, 1.91]), and dementia (OR = 3.21 [95% CI: 1.97, 5.24]) during the comparison between PD patients with and without GBA mutations. While, in the aspect of tremor as an initial symptom (OR = 0.81 [95% CI: 0.64, 1.03]), the severity of motor symptoms such as H-Y (MD = 0.06 [95% CI: −0.06, 0.17]) and UPDRS-III (MD = 1.61 [95% CI: −0.65, 3.87]) and having dyskinesia (OR = 1.60 [95% CI: 0.90, 2.84]) during the comparison between the two groups revealed no statistical differences. Our results suggested that the phenotypes of PD patients with GBA mutations are different from GBA noncarriers.

The rs3756063 polymorphism is associated with SNCA methylation in the Chinese Han population.

Parkinsons disease (PD) is the second most common neurodegenerative disorder. Genome-wide association studies have confirmed the association of single nucleotide polymorphisms (SNPs) located in the SNCA gene with the risk of PD. While hypomethylation of the SNCA intron-1 was observed in patients with sporadic PD, an association between SNCA SNPs and SNCA methylation levels has been identified. To investigate whether these SNPs are associated with the level of SNCA methylation in the Chinese population, we genotyped SNCA SNPs and analyzed the relationship between SNCA SNPs and SNCA DNA methylation status from peripheral blood mononuclear cells of Chinese Han PD patients. Our results revealed that the rs3756063 polymorphism could contribute to the risk of PD in the Chinese Han population and confirmed the effect of this polymorphism on SNCA DNA methylation. Further studies will be needed to gain a better understanding of the mechanisms underlying the associations between SNPs, methylation and PD pathogenesis.

Genetic association study of glucocerebrosidase gene L444P mutation in essential tremor and multiple system atrophy in mainland China

The glucocerebrosidase (GBA) gene mutation is emerging as an important risk factor for Parkinsons disease. We previously reported that the GBA gene L444P mutation is an important risk factor for PD in the Chinese population. The prevalence of this mutation in other neurodegenerative diseases and movement disorders remains completely unexplored in mainland China. In the present study, we extended the screening of GBA gene L444P mutation to Chinese patients with essential tremor (ET) and multiple system atrophy (MSA). We searched for the GBA gene L444P mutation in 109 patients with ET, 54 patients with MSA, and 657 controls from mainland China. None of the 109 patients with ET or 54 patients with MSA carried the GBA gene L444P mutation. Among the 657 controls, we found one L444P heterozygote. The difference in mutation frequencies between patients with ET or MSA and the control group was not statistically significant (chi-squared test, p = 1, respectively). The results suggest that the GBA gene L444P mutation may be not responsible for ET in mainland China. Whether the GBA gene L444P mutation modifies the risk for MSA deserves further study in larger samples.

Lack of association between IL-10 and IL-18 gene promoter polymorphisms and Parkinson’s disease with cognitive impairment in a Chinese population

Inflammatory processes have been implicated in the pathogenesis of Parkinson’s disease (PD), including the development of PD-associated cognitive impairment. Whether genetic variants of inflammatory cytokine genes influence the risk of cognitive impairment in PD is unknown. In this study, we investigated single nucleotide polymorphisms (SNPs) in the IL-10 promoter (rs1800871 and rs1800872) and in the IL-18 promoter (rs1946518 and rs187238) in a Han Chinese cohort (N = 933). PD patients (N = 460) and controls (N = 473) were genotyped. Additionally, 268 PD patients were divided into three subgroups [cognitively normal (PD-NC), mild cognitive impairment (PD-MCI), and with dementia (PD-D)] on the basis of their performance on a battery of neuropsychological tests. No associations were found between the aforementioned polymorphisms and cognitive impairment in PD; thus no confirmatory evidence for the hypothesis of IL-10 and IL-18 alleles modulating the risk of cognitive impairment in Chinese PD patients was obtained.

Genome-wide analysis of DNA methylation during antagonism of DMOG to MnCl2-induced cytotoxicity in the mouse substantia nigra.

Exposure to excessive manganese (Mn) causes manganism, a progressive neurodegenerative disorder similar to idiopathic Parkinson’s disease (IPD). The detailed mechanisms of Mn neurotoxicity in nerve cells, especially in dopaminergic neurons are not yet fully understood. Meanwhile, it is unknown whether there exists a potential antagonist or effective drug for treating neuron damage in manganism. In the present study, we report the discovery of an HIF prolyl-hydroxylase inhibitor, DMOG [N-(2-Methoxy-2-oxoacetyl) glycine methyl ester], that can partially inhibit manganese toxicity not only in the neuroblastoma cell line SH-SY5Y in vitro but also in a mouse model in vivo. A genome-wide methylation DNA analysis was performed using microarray hybridization. Intriguingly, DNA methylation in the promoter region of 226 genes was found to be regulated by MnCl2, while the methylation effects of MnCl2 could be restored with combinatorial DMOG treatment. Furthermore, we found that genes with converted promoter methylation during DMOG antagonism were associated across several categories of molecular function, including mitochondria integrity maintain, cell cycle and DNA damage response, and ion transportation. Collectively, our results serve as the basis of a mechanism analysis of neuron damage in manganism and may supply possible gene targets for clinical therapy.