Parkinson's Disease In Chinese Population Research Articles

No relationship between SRY variants and risk of Parkinson's disease in Chinese population

Parkinson's disease (PD) is a common neurodegenerative disease with inherent sex differences, and sex-determining region Y (SRY) is a gene located in the Y chromosome which encodes a transcription factor involving the regulation of the dopamine system. In this study, we investigated whether SRY variants were associated with PD in Chinese population. A total of 2058 male patients with PD and 1650 male control participants were recruited, and variants in SRY transcript and flanking regions were genotyped by whole-exome sequencing or whole-genome sequencing. Analysis of rare variants by the optimal sequence kernel association test showed no difference in variant burden of coding, 5′-noncoding and 3′-noncoding between the case and control group. In addition, of the 6 common variants identified, none showed a significant effect in altering PD risk in our population using logistic regression. Our results suggested SRY variants were not associated with the risk of PD in Chinese population.

Relationship between variants of 17 newly loci and Parkinson's disease in a Chinese population.

Genetic factors play significant roles in the causes of Parkinson's disease (PD). Recently, a meta-analysis of genome-wide association study (GWAS) has identified 17 loci associated with PD. The objective of our study was to investigate the association of 17 single-nucleotide polymorphisms with the risk of PD in Chinese population. We performed a case-control association study, and 1189 subjects comprising 652 PD patients and 537 controls were genotyped by using a Mass ARRAY System or a TaqMan assay. Wefound that rs601999 (OR (95% CI)= 3.378 (2.273-5.051), p < 0.001), rs11343 (OR (95% CI)= 0.426 (0.210-0.862), p= 0.018), rs353116 (OR (95% CI)= 0.738 (0.577-0.943), p= 0.015), and rs2280104 (OR (95% CI)= 1.371 (1.078-1.743), p= 0.010) were significantly associated with PD in Chinese population. However, no significant association was found in the remaining 13 single-nucleotide polymorphisms between both groups.

Analysis of Single Nucleotide Polymorphisms of STK32B, PPARGC1A and CTNNA3 Gene With Sporadic Parkinson's Disease Susceptibility in Chinese Han Population.

Recently, five novel single nucleotide polymorphisms (SNPs), rs10937625 in STK32B (serine/threonine kinase 32B), rs17590046 in PPARGC1A (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), and rs12764057, rs10822974, and rs7903491 in CTNNA3 (catenin alpha 3), were found to be associated with increased risk of essential tremor (ET) in a genome-wide association study (GWAS)in individuals of Caucasian ancestry. Considering the overlap between ET and Parkinson's disease (PD) in pathological features and clinical manifestations, a case-control study comprising 546 PD patients and 550 control subjects was carried out to examine whether the same variants were also associated with PD in Chinese Han population. However, the above variants did not show an association with PD. Our results suggested that these variants do not play a major role in PD in the Chinese population, Actually, the clinical overlap between PD and ET is under debate. In our Chinese Han cohort, we did not verify potential genetic pleiotropy between two diseases, which may indicated that etiology and pathobiology of PD and ET are distinct. Thus, a more comprehensive study such as a multi-center study may be helpful to evaluate the relationship between the five new susceptible loci and PD in Chinese Han population in the future.

MC1R variants in Chinese Han patients with sporadic Parkinson's disease

Recently, a variant p.R160W in the MC1R gene was identified that increased the risk of Parkinson's disease (PD) in Spanish population. To explore whether the MC1R gene variants are associated with sporadic PD in Chinese population, we performed a case-control comparison study for comprehensive MC1R variant screening in 510 Chinese Han patients and 495 healthy controls as ethnically matched controls. We identify 5 nonsynonymous variants, including rs34090186 (p.R67Q), rs2228479 (p.V92M), rs33932559 (p.I120T), rs885479 (p.R163Q), and rs372152373 (p.R223W). However, variants mentioned previously did not show association with PD. Our results suggest that variants in MC1R do not play a major role in PD in the Chinese population.

NFE2L2 variations reduce antioxidant response in patients with Parkinson disease.

Oxidative stress has been recognized as a risk factor of Parkinson's disease (PD) development. We hypothesized that decreased function of the nuclear factor (erythroid-derived 2)-like 2 (NFE2L2)-antioxidant response element (ARE) pathway might predispose to Parkinsonism. A case-control study was performed between NFE2L2 Single Nucleotide Polymorphism (SNP) and PD in a cohort of 765 unrelated patients with diagnosis of PD and 489 matched normal individuals. We found that c.351T>A, D117E (P = 0.003, OR = 2.8) and c.351T>A, D117E (P = 0.012, OR = 1.9) were significantly associated with PD. The risk allele of both polymorphisms showed a high frequency in our PD sample (c.351A: 19.7% and c.423T: 7.8%). The association between both c.351T>A and c.423G>T and PD was further confirmed in an independent case-control cohort consisting of 210 individuals with PD and 148 normal controls. We further found that over expression of D117E and Q141H variants of NFE2L2 reduced target genes expression of Glutathione S-transferase Pi 1 (GSTP1), Glutathione S-transferase Mu 1 (GSTM1), and Heme oxygenase 1 (HO-1) genes. NFE2L2 D117E and Q141H impaired activation of ARE-driven transcriptional activity. Our findings indicate that NFE2L2 may play an important role in the pathogenesis of PD in Chinese populations.

Association of four new candidate genetic variants with Parkinson's disease in a Han Chinese population.

Large-scale meta-analysis of genome-wide association data has identified six new risk loci (SIPA1L2, INPP5F, MIR4697, GCH1, VPS13C, and DDRGK1) for Parkinson's disease (PD). However, the characteristics of those loci in a Han Chinese population from mainland China are unknown. We examined genetic associations of VPS13C rs2414739, MIR4697 rs329648, GCH1 rs11158026, and SIPA1L2 rs10797576 with PD susceptibility in a Han Chinese population of 1028 sporadic PD patients and 1109 healthy controls. All subjects were genotyped for these loci using the Sequenom iPLEX Assay. We also conducted further stratified analysis according to age at onset and compared the clinical characteristics between minor allele carriers and non-carriers for each locus. However, we did not observe any significant difference in genotype distribution between PD patients and controls for the four loci, even after being stratified by age at onset. Besides, minor allele carriers cannot be distinguished from non-carriers based on their clinical features. Our findings first demonstrated that VPS13C rs2414739, MIR4697 rs329648, GCH1 rs11158026, and SIPA1L2 rs10797576 do not confer a significant risk for PD in Chinese population. Additional replication studies in other populations and functional studies are warranted to better validate the role of the four new loci in PD risk.

No association of FAM47E rs6812193, SCARB2 rs6825004 and STX1B rs4889603 polymorphisms with Parkinson's disease in a Chinese Han population.

Recently, a series of studies found that the single-nucleotide polymorphisms (SNPs) rs6812193 in the family with sequence similarity 47, member E (FAM47E), rs6825004 in the scavenger receptor class B member 2 (SCARB2) and rs4889603 in the Syntaxin1B (STX1B) genes increase the risk for Parkinson's disease (PD). However, the results of subsequent independent studies were inconsistent. To explore the associations between the three SNPs and PD in the Chinese population, a large cohort was analyzed in a case-control study. A total of 1994 subjects, including 1179 PD and 815 healthy controls (HCs), were investigated. All subjects were genotyped for rs6812193, rs6825004 and rs4889603 using the Sequenom iPLEX Assay. There was no significant difference in additive genetic model of rs6812193, rs6825004 and rs4889603 between PD and controls, even after being stratified by sex and age. In addition, no significant differences were found between other subgroups of PD patients with regard to clinical presentation. Our findings suggested that FAM47E rs6812193, SCARB2 rs6825004 and STX1B rs4889603 do not confer a significant risk for PD in Chinese population.

LRRK2 A419V variant is a risk factor for Parkinson's disease in Asian population

Recently, LRRK2 A419V (rs34594498) was reported associating with Parkinson's disease (PD) in Asian population; yet the conclusion is still unobvious. We conducted a case-control study to determine the potential associations between A419V and PD in Chinese population. Five hundred PD patients and 574 health controls were genotyped. Our results showed, A419V has a significantly higher frequency among PD patients than the controls (p = 0.025, odds ratio [OR] = 2.57, 95% confidence interval [CI] [1.13–5.86]), especially in early-onset PD (p = 0.027, OR = 10.40, 95% CI [1.31–82.89]). And PD patients who carried A419V have a lower Minimum-Mental State Examination scores than PD patients who did not (p = 0.04). We also conducted a meta-analysis on A419V. In Asian population, A419V was detected at a significantly higher frequency among PD patients in contrast to controls: Z = 2.47, p = 0.01, OR = 2.11, 95% CI [1.17–3.82]. When only considering the Chinese population, the difference was more obvious with Z = 3.41, p = 0.0007, OR = 2.07, 95% CI [1.36–3.14]. The results suggest LRRK2 A419V appears to be a risk factor for PD in Asian, especially in early-onset patients. Finally, larger sample with centering on young or cognitive impairment PD patients in Asian would be preferable for further confirmation.

Genetic analysis of the RAB39B gene in Chinese Han patients with Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder of complex etiology. Mounting evidence indicates that genetic abnormalities play an important role in the pathogenesis of PD. To date, at least 20 genetic loci and 15 disease-causing genes for parkinsonism have been identified, as well as some susceptibility genes conferring risk to PD. More recently, mutations in the RAB39B gene (RAB39B, member RAS oncogene family) have been reported to cause X-linked intellectual disability and early-onset PD with α-synuclein pathology. To evaluate whether variants in the RAB39B gene are related to PD in Chinese Han population, we conducted genetic analysis of the RAB39B gene in 502 patients with PD from Mainland China. No pathogenic mutation or variant was identified in the coding region or exon-intron boundaries of the gene. Our results suggest that mutation(s) in the coding region of the RAB39B gene plays little or no role in the development of PD in Chinese population.

Genetic analysis of SNCA coding mutation in Chinese Han patients with Parkinson disease.

Parkinson disease (PD) is the second most common progressive neurodegenerative disorder. It is characterized by selective loss of dopamine-producing neurons and aggregation of alpha-synuclein (SNCA) in neurons of particular brain regions. At least 20 loci and 15 disease-causing genes have been identified. Rare missense or multiplication mutations in the SNCA gene have been reported to be involved in some familial and sporadic cases of PD. More recently, two novel pathogenic missense mutations (p.H50Q and p.G51D) were identified in the SNCA gene. To evaluate whether mutation(s) in the coding region of SNCA gene is related to PD in Chinese population, we investigated the SNCA gene in 502 PD patients of Chinese Han ethnicity from Mainland China. No pathogenic mutation was identified in the coding region of the gene. A known G to A transition (c.306 + 66G>A, rs10005233) in the intron 4, which does not potentially change splicing, was identified. Our data indicate that mutations in the coding region of the SNCA gene are not likely to be a common cause of PD in Chinese population.

Genetic analysis of the S100B gene in Chinese patients with Parkinson disease

There is growing evidence that genetic abnormalities play an important role in the pathogenesis of Parkinson disease (PD). At least 18 genetic loci and 13 disease-related genes for parkinsonism have been identified. The S100 calcium-binding beta (S100B), which is expressed and secreted by astrocytes, has been found to be associated with PD. To evaluate whether the S100B variants are related to PD in Chinese Han population, we conducted genetic examination of the S100B gene in 502 PD patients from Mainland China. We did identify two known variants c.279+4T>C (rs187503470) and c.99C>G (p.Leu33Leu, rs1051169) in our patients. Neither of these two variants is predicted to change amino acid or splice site, indicating that they are not pathogenic mutations. Our results suggest that mutations in the coding region or intron/exon boundaries of the S100B gene play little or no role in the development of PD in Chinese population.

Marginal association between SNP rs2046571 of the HAS2 gene and Parkinson's disease in the Chinese female population

Recent GWASs have implicated many novel SNPs in the development of Parkinson's disease (PD). Single nucleotide polymorphism (SNP) rs2046571 of the HSA2 (encoding hyaluronan synthase 2) was reported to have marginal association with PD. Herein, we conducted a case–control study to evaluate the possible association between SNP rs2046571 and PD in Chinese. All subjects (1043 PD patient and 1044 normal control) were successfully genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. No statistically significant difference in genotype frequency between cases and controls was observed (P=0.074), no statistically significant difference in genotype frequency between early-onset and late-onset was observed (P=0.264 and P=0.120, respectively). No statistically significant difference in genotype frequency between male cases and controls (P=0.108). But surprisingly, there was statistically marginal significant difference in genotype frequency between female cases and controls (P=0.042). Our findings suggested that rs2046571 of the HSA2 has marginal association with PD in Chinese population.

Association of Mitochondrial DNA Polymerase γ Gene POLG1 Polymorphisms with Parkinsonism in Chinese Populations

BackgroundMitochondrial DNA polymerase gamma (POLG1) mutations were associated with levodopa-responsive Parkinsonism. POLG1 gene contains a number of common nonsynonymous SNPs and intronic regulatory SNPs which may have functional consequences. It is of great interest to discover polymorphisms variants associated with Parkinson's disease (PD), both in isolation and in combination with specific SNPs.Materials and MethodsWe conducted a case-control study and genotyped twenty SNPs and poly-Q polymorphisms of POLG1 gene including in 344 Chinese sporadic PD patients and 154 healthy controls. All the polymorphisms of POLG1 we found in this study were sequenced by PCR products with dye terminator methods using an ABI-3100 sequencer. Hardy-Weinberg equilibrium and linkage disequilibrium (LD) for association between twenty POLG1 SNPs and PD were calculated using the program Haploview.Principal ResultsWe provided evidence for strong association of four intronic SNPs of the POLG1 gene (new report: c.2070-12T>A and rs2307439: c.2070-64G>A in intron 11, P = 0.00011, OR = 1.727; rs2302084: c.3105-11T>C and rs2246900: c.3105-36A>G in intron 19, P = 0.00031, OR = 1.648) with PD. However, we did not identify any significant association between ten exonic SNPs of POLG1 and PD. Linkage disequilibrium analysis indicated that c.2070-12T>A and c.2070-64G>A could be parsed into one block as Haplotype 1 as well as c.3105-11T>C and c.3105-36A>G in Haplotype 2. In addition, case and control study on association of POLG1 CAG repeat (poly-Q) alleles with PD showed a significant association (P = 0.03, OR = 2.16) of the non-10/11Q variants with PD. Although intronic SNPs associated with PD didn't influence POLG1 mRNA alternative splicing, there was a strong association of c.2070-12T>A and c.2070-64G>A with decreased POLG1 mRNA level and protein levels.ConclusionsOur findings indicate that POLG1 may play a role in the pathogenesis of PD in Chinese populations.

Association of PITX3 polymorphism with Parkinson's disease in Chinese patients

Objective To investigate the relationship between polymorphism in the PITX3 gene and hereditary susceptibility of Parkinson's disease(PD). Methods Three PITX3 single nucleotide polymorphisms (SNPs), including rs2281983, rs4919621 and rs3758549 were examined in 509 late-onset PD patients(LOPD), 290 early-onset PD(EOPD) and 494 healthy controls. Genotyping was carried out in all subjects using a ligase detection reaction(LDR). Results Allele and genotype frequencies did not differ between the 799 PD patients and 494 controls(P values of genotype were 0.494, 0.343, 0.951; P values of allele were 0.369, 0.297, 0.823), between 509 LOPD patients and 494 controls(P values of genotype were 0.522, 0.350, 0.630; P values of allele were 0.413, 0.328, 0.571), between 290 EOPD patients and 494 controls(P values of genotype were 0.499, 0.492, 0.552; P values of allele were 0.321, 0.301, 0.931), and between 509 LOPD and 290 EOPD patients(P values of genotype were 0.577, 0.710, 0.127; P values of allele were 0.346, 0.472, 0.077) for all three SNPs (rs2281983, rs4919621 and rs3758549). There were no association petween the three PITX3 SNPs and PD. Conclusion Three PITX3 SNPs do not contribute to the risk of developing PD in Chinese population. Key words: PITX3 gene; Late-onset Parkinson's disease; Early-onset Parkinson's disease; Single nucleotide polymorphisms

Association study between two novel single nucleotide polymorphisms and sporadic Parkinson's disease in Chinese Han population

Two novel single nucleotide polymorphisms (SNPs) (rs6812193 and rs11868035) were recently identified to be associated with Parkinson's disease (PD) in a Web Based Genome-Wide Association Study. Herein, we conducted a case–control study to evaluate the possible associations between these two SNPs and PD in Chinese Han population. All subjects (501 sporadic PD patients and 502 normal controls) were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis with these two SNPs. Chi-square test revealed no significant difference in either genotype frequencies or allele frequencies, even after being stratified by age. But we found that the genotype and allele frequency of rs6812193 shows difference between male patients and male controls (p=0.031, OR=0.584; p=0.037, OR=0.606) but none in the female. Our findings suggest that rs11868035 may have no association with PD in Chinese population and rs6812193 may have marginal association with PD in male Chinese population. However, due to the limited data in the present study, replication studies in larger sample and other populations are required.

Vacuolar protein sorting 35 Asp620Asn mutation is rare in the ethnic Chinese population with Parkinson's disease

Vacuolar protein sorting 35 (VPS35) Asp620Asn mutation has been identified in late-onset familial Parkinson's disease (PD) patients of Swiss and Austrian descent as well as sporadic PD patients in the United States. In order to determine the contribution of VPS35 mutations in mainland Chinese PD patients and to better understand the association between VPS35 and PD, we sequenced all 17 exons of VPS35 in 32 probands of presumed autosomal-dominant, late-onset familial PD and 35 normal controls. Meanwhile, we analyzed VPS35 Asp620Asn mutation in 512 PD patients. A total of 371 subjects without neurological disorders from the same region in China were set as a control group. We did not find any VPS35 coding region mutation in 32 familial PD patients. VPS35 Asp620Asn mutation was either not found in 480 PD patients. Our results suggested that VPS35 Asp620Asn may be not associated with PD in Chinese population.

HLA rs3129882 variant in Chinese Han patients with late-onset sporadic Parkinson disease

Recently, the rs3129882 variant in intron 1 of HLA-DRA was found to be associated with late-onset sporadic Parkinson disease (PD) in Americans of European ancestry. To evaluate whether the same variant is related to PD in Chinese population, we investigated late-onset sporadic PD patients of Chinese Han ethanicity in Mainland China. We found significant difference in genotypic and allele distribution between patients and control subjects (χ2=6.446, p=0.040 for genotypic distribution; χ2=5.762, p=0.016 for allele distribution), suggesting this variant is associated with late-onset sporadic PD in Chinese Han population.

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 Parkinson's 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.