Parkinson's Disease In Asian Populations Research Articles

Analysis of 12 GWAS-Linked Loci With Parkinson's Disease in the Chinese Han Population.

A recent large-scale European-originated genome-wide association study identified 38 novel independent risk signals in 37 loci for Parkinson's disease (PD). However, whether these new loci are associated with PD in Asian populations remains elusive. The present study aimed to explore the relationship between the 12 most relevant loci with larger absolute values for these new risk loci and PD in the Chinese Han population. We performed a case-control study including 527 PD patients and 435 healthy controls. In the allele model, it was found that rs10748818/GBF1 was associated with PD in the Chinese Han population [p = 0.035, odds ratio (OR) 1.221, 95% confidence interval (CI) 1.014–1.472

Association between vitamin D receptor polymorphisms and susceptibility to Parkinson's disease: An updated meta-analysis

The relationships between vitamin D receptor (VDR) gene polymorphisms, particularly ApaI, BsmI, FokI, and TaqI, and Parkinson's disease (PD) has received increasing attention in the research community. However, as the results yielded by this increased research have hitherto conflicted, we performed an updated meta-analysis of reports on the relationships between VDR polymorphisms and PD published before October 2019 that we collected from the PUBMED, EMBASE, EBSCO, China National Knowledge Infrastructure (CNKI), and Wanfang databases. The ten articles that met our screening criteria included 2782 patients and 3194 healthy controls. All the data that we received were analyzed with Stata 12.0 statistical software. The odds ratio (OR) and 95 % confidence intervals (CIs) were used to determine the relationship between VDR gene diversity and PD. While we did not find a significant correlation between the ApaI, BsmI, and TaqI polymorphisms and the risk of PD in any of the considered genetic models, we found a clear association between the FokI polymorphism and susceptibility to PD (C vs. T: OR = 1.246, 95 % CI: 1.101–1.411, P = 0; CC vs. TT: OR = 1.630, 95 % CI: 1.243–2.139, P = 0; CT vs. TT: OR = 1.382, 95 % CI: 1.059–1.804, P = 0.017; CC + CT vs. TT: OR = 1.491, 95 % CI: 1.159–1.919,P = 0.002; CC vs. CT + TT: OR = 1.261, 95 % CI: 1.062–1.496, P = 0.008). Our subgroup analysis performed according to ethnicity revealed that FokI increased the risk of PD in Asian populations (C vs. T: OR = 1.261, 95 % CI: 1.080–1.472, P = 0.003; CC vs. TT: OR = 1.664, 95 % CI: 1.189–2.330, P = 0.003; CT vs.TT: OR = 1.387, 95 % CI: 1.000–1.925, P = 0.05; CC + CT vs. TT: OR = 1.497, 95 % CI: 1.098–2.042, P = 0.011; CC vs. CT + TT: OR = 1.285, 95 % CI: 1.036–1.593, P = 0.022). Overall, the gene polymorphism of FokI only increases the risk of PD among Asian populations. Given the limited sample size of this study, the findings should be carefully explained.

The association between CD157/BST1 polymorphisms and the susceptibility of Parkinson's disease: a meta-analysis.

Background: Different studies have provided some evidence for the association between BST1 polymorphisms and Parkinson’s disease (PD). The extent to which these genetic effects are consistent across different populations is unknown.Methods: A meta-analysis of PD case-control studies using a common set of three variants was conducted. Published reports were obtained from electronic databases including Pubmed, Embase, Chinese National Knowledge Infrastructure (CNKI) and Cochrane Library databases between August 2010 and January 2018.Results: A total of 11 individual studies with 8,725 cases and 17,079 controls were included. The results showed statistically significant association between the dominant model of rs11931532 and PD risk in Asian populations (P=0.006, OR [95% CI]=1.22 [1.06–1.41]). Significant association was also detected between the allelic, dominant, and recessive models of rs4698412 and PD risk in Asian populations (allelic model: P<0.00001, OR [95% CI]=1.22 [1.16–1.29]; dominant model: P<0.00001, OR [95%CI]=1.35 [1.20–1.52]; recessive model; P=0.0003, OR [95% CI]=1.30 [1.13–1.50]). Nevertheless, the pooled analyses suggested that no significant association was uncovered between rs11724635 and PD risk (P>0.05).Conclusion: The meta-analysis suggests that the rs11931532 and rs4698412, but not rs11724635 might be risk factors for PD in Asian populations.

The genetic association between apolipoprotein E gene polymorphism and Parkinson disease: A meta-Analysis of 47 studies.

Although the relationship between apolipoprotein E (ApoE) gene polymorphisms and the risk of Parkinson disease (PD) has been established, the results were inconsistent and inconclusive. A comprehensive search examining the association between APOE polymorphisms and PD through PubMed, Embase, Chinese National Knowledge Infrastructure (CNKI), and Cochrane Library databases was performed without published year limited. A total of 47 studies with 7533 cases and 14442 controls were included in present study. The results showed statistically significant association between risk factor ApoE ε4 allele and PD in Asian population (P = .003, odds ratio, OR [95% confidence interval, CI] = 1.43 [1.13,1.80]). Genotype ε2ε4 have significantly associated with PD in Asian population (P = .004, OR [95% CI] = 4.43 [1.62,12.10]). Genotype ε3ε4 was significantly associated with PD in Latin-American population (P = .01, OR [95% CI] = 1.44 [1.08,1.91]). In addition, the frequency of the genotype ε3ε4 is lower in PD group than that in the control group in Caucasian population, and the difference of genotype ε3ε4 is also statistically significant (P = .006, OR [95% CI] = 0.86 [0.77,0.96]). Although significant heterogeneity was observed among all studies, the results were shown to be stabilized by sensitive analysis. No publish bias was observed. This meta-analysis suggests that the APOE ε4, but no ε2, might be a risk factor for PD in Asian population. Furthermore, the genotype ε2ε4 may be a susceptible factor for PD in Asian population, and the genotype ε3ε4 may be a susceptible factor for PD in both Caucasian and Latin-American populations.

Association analyses of variants of SIPA1L2, MIR4697, GCH1, VPS13C, and DDRGK1 with Parkinson's disease in East Asians.

A recent large-scale European-originated genome-wide association data meta-analysis followed by a replication study identified 6 new risk loci for Parkinson's disease (PD), which include rs10797576/SIPA1L2, rs117896735/INPP5F, rs329648/MIR4697, rs11158026/GCH1, rs2414739/VPS13C, and rs8118008/DDRGK1. However, whether these new loci are associated with PD in Asian populations remain elusive. The INPP5F is nonpolymorphic in Asians. The present study aimed to understand the effects of the other 5 new loci in a Han Chinese population comprising 579 sporadic PD patients and 642 controls. Significant associations with PD were observed in the variants of SIPA1L2 (p= 0.001) and VPS13C (p= 0.007), where the T (odd ratio [OR]= 1.484, 95% confidence interval [CI] 1.186-1.858) and A (OR= 1.362, 95% CI 1.087-1.707) alleles serve as the risk alleles, respectively. The genotype distributions in the SIPA1L2 and VPS13C variants were also different between the patients and controls (p= 0.002 and p= 0.023, respectively). In contrast, no significant association with PD was found in the variants of MIR4697, GCH1, and DDRGK1 either in allele or genotype frequencies. Noteworthy, a followed meta-analysis of East Asian studies suggested an association of the GCH1 variant with PD (p= 0.04, OR 1.08, 95% CI 1.00-1.16), while the other results are in line with those of our cohort. In conclusion, our study together with meta-analyses demonstrates that the variants of SIPA1L2 and VPS13C, potentially GCH1, but not of MIR4697 and DDRGK1, are associated with PD susceptibility in East Asians.

Leucine-Rich Repeat Kinase (LRRK2) Genetics and Parkinson's Disease.

The discovery of LRRK2 mutations as a cause of Parkinson's disease (PD), including the sporadic late-onset form, established the decisive role of genetics in the field of PD research. Among LRRK2 mutations, the G2019S, mostly lying in a haplotype originating from a common Middle Eastern ancestor, has been identified in different populations worldwide. The G2385R and R1628P variants represent validated risk factors for PD in Asian populations. Here, we describe in detail the origin, the present worldwide epidemiology, and the penetrance of LRRK2 mutations. Furthermore, this chapter aims to characterize other definitely/probably pathogenic mutations and risk variants of LRRK2. Finally, we provide some general guidelines for a LRRK2 genetic testing and counseling. In summary, LRRK2 discovery revolutionized the understanding of PD etiology and laid the foundation for a promising future of genetics in PD research.

Genetic Analysis of LRRK2 R1628P in Parkinson's Disease in Asian Populations.

Although the etiology of Parkinson's disease (PD) remains unclear, there is increasing evidence of genetic factors contributing to the onset of PD. Various mutations and risk variants of the gene LRRK2 have been reported, but the association between LRRK2 R1628P and PD is still inconsistent. Thus, we conducted a meta-analysis to determine the potential relationship between R1628P and PD. Our study sample was an aggregate of 17 publications, which in total consisted of 9,275 PD patients and 8,114 controls. All of these articles are of high quality according to NOS, and there was no obvious reporting bias or heterogeneity. In a general Asian population, the pooled OR of the risk genotype contrasts was 1.83 (95% CI: 1.57, 2.13). When stratified by ethnicity, the pooled ORs were 1.84 (95% CI: 1.56, 2.18) in a Chinese population and 1.79 (95% CI: 1.27, 2.52) in a non-Chinese population. Our study suggests that LRRK2 R1628P appears to be a risk factor for PD in Asian populations, both Chinese and non-Chinese.

Relationship between LRRK2 R1628P polymorphism and Parkinson's disease in Asian populations

Although the leucine-rich repeat kinase 2 (LRRK2) R1628P polymorphism has been associated with the risk of Parkinson's disease (PD) in Taiwan, China, and Singapore, there are conflicting findings regarding this relationship. Thus, the aim of the present meta-analysis was to evaluate the associations between the LRRK2 R1628P polymorphism (rs33949390) and PD in Asian populations. A search for eligible studies was performed in PubMed, Embase, SinoMed, and the China Knowledge Resource Integrated Database, and pooled odds ratios and 95% confidence intervals were used to evaluate the strength of the association between the R1628P polymorphism and PD. This meta-analysis assessed 19 studies from 14 papers that involved a total of 9,927 PD patients and 8,602 controls and found that the R1628P polymorphism was significantly associated with the risk of PD in Asian populations. Moreover, stratification analyses indicated that the R1628P polymorphism was significantly associated with an increased risk of PD among Chinese as well as non-Chinese Asian populations and an increased risk of PD in Chinese patients from China, Taiwan, and Singapore. In a stratified analysis conducted according to age, significant associations were found for both late-onset PD and early-onset PD. The present data indicate that the R1628P polymorphism of the LRRK2 gene contributes to PD susceptibility in Asian, especially Chinese, populations.

An association analysis of the R1628P and G2385R polymorphisms of the LRRK2 gene in multiple system atrophy in a Chinese population.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been reported to be responsible for autosomal dominant late-onset sporadic Parkinson's disease (PD). The R1628P and G2385R polymorphisms of the LRRK2 gene have been identified as exclusively associated with PD in Asian populations, particularly in Han Chinese population. Considering that there is overlap of the clinical manifestations and pathological characteristics between PD and MSA, we studied the possible associations between R1628P and G2385R polymorphisms of the LRRK2 and MSA in a population of Han Chinese patients. A total of 318 MSA patients and 350 unrelated age- and sex-matched healthy controls (HCs) were included in the study. All subjects were genotyped for R1628P and G2385R using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis and direct sequencing. No significant differences were observed in the genotype distribution and minor allele frequency (MAF) of R1628P between MSA patients and HCs (P = 0.418 and P = 0.424), between MSA-C and HCs (P = 0.347 and P = 0.353), between MSA-P and HCs (P = 0.787 and P = 0.790), and between MSA-C and MSA-P (P = 0.606 and P = 0.610). In addition, no significant differences were also observed in the genotype distribution and MAF of G2385R between MSA patients and HCs (P = 0.141 and P = 0.051), between MSA-C and HCs (P = 0.061 and P = 0.065), between MSA-P and HCs (P = 0.184 and P = 0.158), and between MSA-C and MSA-P (P = 0.354 and P = 0.853). The present study suggests that R1628P and G2385R polymorphisms of the LRRK2 are not risk factors for MSA in the Han Chinese population.

LRRK2 G2385R variant carriers of female Parkinson’s disease are more susceptible to motor fluctuation

The relation between the LRRK2 mutation and its effect on Parkinson's disease (PD) has always caught a lot attention. Recent studies found that the G2385R polymorphism of LRRK2 may increase the risk of PD in Asian populations. Here we tried to clarify the relationship between the LRRK2 G2385R variant and the clinical profiles including motor complication in Chinese PD patients. We identified the LRRK2 variant in the Chinese Han population in northern China and evaluated the relationship between the G2385R variant and clinical profiles through comparison between 36 carriers and 139 non-carriers. We found that G2385R carriers scored significantly higher in motor fluctuation and dyskinesia than non-carriers. Logistic regression analysis showed that the G2385R variant was an independent risk factor for motor fluctuation in females (odds ratio=12.538, 95% CI2.216-70.942, P=0.004), and a Chi-squared test showed that the frequency of dyskinesia tended to be higher in the carrier group compared to the non-carrier group (16 vs. 4.4%, P=0.050, OR=4.127, 95% CI1.074-15.864). These findings indicate that the variant was closely related to the occurrence of motor complication. Additionally, the G2385R variant was significantly related to the early-onset of PD in female carriers (20.0 vs. 1.5%, odds ratio=16.25, 95% CI 1.557-169.618, P=0.020). Our study found that the G2385R variant was significantly associated with motor complications and that this variant was an independent risk factor for motor fluctuation in females. These findings provide the necessary preliminary data to better understand the unique profile of PD G2385R variant carriers.

Leucine-rich repeat kinase 2-linked Parkinson's disease: clinical and molecular findings.

Mutations in Leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of sporadic and familial late onset Parkinson’s disease (PD). The G2019S common mutation has been identified about 1% of sporadic cases and 4–7% of familial cases. Over 50 variants have since been identified in LRRK2, and at least 7 of these are confirmed to be pathogenic. In addition to pathogenic mutations, several common polymorphisms in the LRRK2 gene (G2385R and R1628P) have been identified that may explain up to 10% of sporadic PD in Asian populations. LRRK2 is a large complex multidomain protein with 2,527-amino-acid and the molecular weight is 286 kDa. LRRK2 multidomain protein consists of a catalytic core domain, kinase domain and a number of putative protein-protein interaction domains. LRRK2 mutations found in PD families, including the G2019S and I2020T mutations show increased intrinsic kinase activity, when assessed with myelin basic protein as substrate. The modification of LRRK2 GTPase and kinase activity affecting residues in the ROC, COR and mitogen-activated protein kinase kinase kinases domains is believed to lead to neuronal cell death, but the pathways involved remain unclear. A number of in vivo models in C. elegans, D. melanogaster and mice have been developed to study the patho/physiological function of LRRK2. Based on current literature, a toxic gain of function in LRRK2 kinase activity is a possible pathophysiologic mechanism and thus inhibition of kinase activity in experimental models offers a potential therapeutic strategy for LRRK2-linked PD.

Clinical features of LRRK2 parkinsonism

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene were initially identified in large families with autosomal dominant Parkinson disease (PD). These mutations (p.R1441C, p.R1441G, p.Y1699C and p.I2020T) revealed that genetic mutations could cause clinically typical, late-onset PD. Subsequently, the p.G2019S mutation was found to be a frequent cause of both autosomal dominant and "sporadic" PD, particularly in populations in North Africa or the Middle East. Two Lrrk2 protein substitutions (p.R1628P and p.G2385R) have since been associated with susceptibility to PD in Asian populations. More than a hundred variants have been identified in the LRRK2 gene, but pathogenicity is most convincing for the p.R1441H substitution. The role in PD remains unknown for other variants because segregation with disease has not been shown. Screening these variants in very large patient-control series may help clarify their role in PD. Lrrk2 is a large, multidomain protein with pathogenic mutations occurring in several functional domains. Cell biological experiments have shown that the p.G2019S mutation increase kinase activity. This is consistent with the observation that homozygous p.G2019S carriers do not have earlier disease onset or more severe disease compared with heterozygous carries. It is now necessary to identify the regulators and substrates of Lrrk2 in order to understand the effect of each LRRK2 mutation. The identification of a large number of presymptomatic LRRK2 mutation carriers provides a unique possibility for future studies on neuroprotection. However, more insight into the basic function of Lrrk2 is needed in order to exploit this potential for translational research.

Update on the Functional Biology of Lrrk2

The etiology of Parkinson's disease (PD) was long thought to be due to environmental factors. Following the discovery of autosomal-dominant mutations in the α-synuclein gene, and later recessive mutations in the DJ-1, Parkin and PINK-1 genes, the field of PD genetics exploded. In 2004, it was discovered that mutations in the PARK8 locus - leucine-rich repeat kinase 2 (LRRK2, Lrrk2) - are the most important genetic cause of autosomal-dominant PD. Lrrk2 substitutions also account for sporadic PD in certain ethnic populations and have been shown to increase the risk of PD in Asian populations. Drug therapies targeting Lrrk2 activity may therefore be beneficial to both familial and sporadic PD patients, hence understanding the role of Lrrk2 in health and disease is critical. This review aims to highlight the research effort concentrated on elucidating the functional biological role of Lrrk2, and to provide some future therapeutic perspectives.

P.5.d.001 Expression of alpha-synuclein in patients with Parkinson's disease caused by mutations in the LRRK2 gene

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene were initially identified in large families with autosomal dominant Parkinson disease (PD). These mutations (p.R1441C, p.R1441G, p.Y1699C and p.I2020T) revealed that genetic mutations could cause clinically typical, late-onset PD. Subsequently, the p.G2019S mutation was found to be a frequent cause of both autosomal dominant and “sporadic” PD, particularly in populations in North Africa or the Middle East. Two Lrrk2 protein substitutions (p.R1628P and p.G2385R) have since been associated with susceptibility to PD in Asian populations. More than a hundred variants have been identified in the LRRK2 gene, but pathogenicity is most convincing for the p.R1441H substitution. The role in PD remains unknown for other variants because segregation with disease has not been shown. Screening these variants in very large patient-control series may help clarify their role in PD. Lrrk2 is a large, multidomain protein with pathogenic mutations occurring in several functional domains. Cell biological experiments have shown that the p.G2019S mutation increase kinase activity. This is consistent with the observation that homozygous p.G2019S carriers do not have earlier disease onset or more severe disease compared with heterozygous carries. It is now necessary to identify the regulators and substrates of Lrrk2 in order to understand the effect of each LRRK2 mutation. The identification of a large number of presymptomatic LRRK2 mutation carriers provides a unique possibility for future studies on neuroprotection. However, more insight into the basic function of Lrrk2 is needed in order to exploit this potential for translational research.

Leucine-Rich Repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population

To assess the effect of genetic factors on sporadic Parkinson disease, we performed a case-control study of a variant (G2385R) in Leucine-Rich Repeat kinase 2 among the Japanese population. The G2385R (c.7153G>A) variant was reported as a risk factor for sporadic Parkinson disease in the Chinese population from Taiwan and Singapore. Genotyping was conducted in 448 Parkinson disease patients and 457 healthy controls. The frequency of A allele in Parkinson disease was significantly higher than in the control (P=1.24x10(-4), odds ratio 2.63, 95% confidence interval 1.56-4.35). Our results suggest that the G2385R variant is a risk factor for sporadic Parkinson disease in the Asian population.