Association of polymorphisms in the elastin gene with sporadic ruptured intracranial aneurysms and unruptured intracranial aneurysms in Chinese patients.

It has been suggested that the elastin gene is a candidate gene for the development of intracranial aneurysms (IAs). We investigated the association of single-nucleotide polymorphisms (SNPs) in the elastin gene in sporadic subarachnoid hemorrhage and in patients with unruptured aneurysms in China. We genotyped 446 (47.9%) IA patients (308 ruptured and 138 unruptured) and 485 (52.1%) control subjects for seven exonic and intronic SNPs in the elastin gene and then evaluated their allelic associations with sporadic ruptured and unruptured IAs. We found that IA is associated with two SNPs in the elastin gene: rs2071307 (odds ratio 2.87; 95% confidence interval, 2.26-3.64; p < 0.001) and rs2856728 (odds ratio 2.12; 95% confidence interval, 1.71-2.62; p < 0.001). Furthermore, the minor allele of rs2071307 (allele A) was also associated with IA rupture; 31.3% of patients with ruptured IAs were carriers of the minor allele, whereas only 23.2% of patients with unruptured IAs carried the minor allele (odds ratio 1.51; 95% confidence interval, 1.09-2.10; p = 0.013). In conclusion, our study indicates that the elastin gene may be associated with the formation of IAs, and importantly, that it may also be associated with the rupture of IAs.

SNCA rs356219 variant increases risk of sporadic Parkinson's disease in ethnic Chinese.

Alpha-synuclein gene (SNCA) polymorphisms have been associated with Parkinson's disease (PD). A recently published genome-wide association study (GWAS) meta-analysis from the USA and Europe found a strong association between SNCA rs356219 and PD. Considering the population-specific heterogeneity, we investigated the role of SNCA rs356219 as PD susceptibility in a large Han Chinese population of 685 patients and 569 controls. The SNCA rs356219-G allele was found to increase the risk to develop PD (OR = 1.81, 95% CI: 1.54-2.13, P = 5.71E-13). The meta-analysis revealed that the frequency of AG + GG genotypes higher in PD than in control subjects (OR = 1.85, 95% CI: 1.56-2.19, P = 0.00001) in the Asian population. PD patients with AG + GG genotypes were associated with earlier age at onset compared with those with AA genotype. No such significant association was observed in the clinical presentation for gender, age at onset, and onset symptoms. Our study provides strong support for the susceptibility role of SNCA rs356219 in sporadic PD in a Han Chinese population from mainland China and the meta-analysis also revealed a similar finding in the Asian population.

GWAS-linked GAK locus in Parkinson's disease in Han Chinese and meta-analysis.

Genome-wide association studies of Parkinson's disease (PD) have recently identified a new susceptibility locus GAK (PARK17) (rs1564282 variant) in subjects of European ancestry. Its role in other races is still unclear. The potential differences of the clinical characteristics between carriers and non-carriers have not been examined in detail. Using a case-control methodology, we analyzed the GAK rs1564282 variant in an ethnic Han Chinese population and conducted a meta-analysis combining our result and available published data. A total of 1,574 ethnic Han Chinese study subjects comprising 812 sporadic PD patients and 762 control individuals were included. The minor allele frequency was significantly different at SNP rs1564282 between the cases and the controls (OR = 1.59, 95% CI = 1.09, 1.69, P = 0.007) in the overall PD population. Subjects with CT + TT genotypes have an increased risk (OR = 1.34, 95% CI = 1.05, 1.72, P = 0.017) compared to those with CC genotype. A meta-analysis revealed that the frequency of carrier's genotypes was significantly higher in PD than in control subjects (OR = 1.31, 95% CI = 1.19, 1.44, P < 0.00001). The gender, age of onset, Hoehn-Yahr stage and UPDRS scores and clinical features were similar between carriers and non-carriers. In conclusion, we demonstrated that the rs1564282 variant in GAK (PARK17) increases the risk of PD in Han Chinese patients from mainland China and the meta-analysis with European populations revealed a similar finding. However, carriers cannot be distinguished from non-carriers based on their clinical features or motor severity. Functional studies of GAK to unravel its role in the pathophysiologic pathway of PD will be useful.

GSK3ß reduces risk of sporadic Parkinson's disease in ethnic Chinese.

Genetic variability of glycogen synthase kinase-3ß (GSK3ß) may be linked to Parkinson's disease (PD). Its role in ethnic Chinese population is still unclear. We examined the association between GSK3ß variation and PD in a Han Chinese population from mainland China. Using a case-control methodology, we genotyped the single nucleotide polymorphism (SNP) in GSK3ß (rs334558) to investigate the association with risk of PD. A total of 1,280 ethnic Han Chinese study subjects comprising 761 sporadic PD patients and 519 controls were recruited. The T allele of a promoter SNP rs334558 was found to reduce the risk of PD (OR = 0.82, 95% CI: 0.696-0.960, P = 0.014). Patients with CT + TT genotypes have a reduced risk of PD compared to those with CC genotype (OR = 0.61, 95% CI: 0.477-0.776, P = 6.09E-5). In addition, we demonstrated that CT + TT subjects cannot be distinguished from CC subjects based on their clinical features. Our data suggest that rs334558 variant in GSK3ß reduces the risk of PD in a Han Chinese population from mainland China. Further studies of large series of subjects are necessary to fully elucidate the true role of GSK3ß in PD.

Association of GWAS loci with PD in China.

Genome-wide association studies (GWAS) have identified numerous single-nucleotide polymorphisms (SNPs) at four loci (SNCA, PARK16, LRRK2, BST1) that can modulate the risk of Parkinson's disease (PD). The strength of these associations has yet to be clarified in Mainland China. Ethnic specific effect is an important consideration in GWAS analysis. Using a case-control methodology, we genotyped multiple SNPs at these four loci to investigate their association with risk of PD in Mainland China. A total of 1,146 study subjects comprising 636 patients with PD and 510 unrelated healthy controls were recruited. The minor alleles at SNPs rs894278, rs1994090, rs2046932, rs4698412, and rs7304279 were found to be significantly higher in cases than in controls, while the minor alleles were found to significantly reduce the risk of developing PD at SNPs rs823128, rs823156, rs6532194, rs1191532, and rs16856139. These associations remained after taking into considerations the effects of age and gender. We showed that multiple SNPs at LRRK2 and SNCA increase risk of PD, while PARK16 SNPs are associated with a lower risk of PD in China. Our study findings will contribute to further research using GWAS-linked data and research on ethnic specific effect of common variants.

Multiple LRRK2 variants modulate risk of Parkinson disease: a Chinese multicenter study.

We and others found two polymorphic LRRK2 (leucine-rich repeat kinase 2) variants (rs34778348:G>A; p.G2385R and rs33949390:G>C; p.R1628P) associated with Parkinson disease (PD) among Chinese patients, but the common worldwide rs34637584:G>A; p.G2019S mutation, was absent. Focusing exclusively on Han Chinese, we first sequenced the coding regions in young onset and familial PD patients and identified 59 variants. We then examined these variants in 250 patients and 250 control subjects. Among the 17 polymorphic variants, five demonstrated different frequency in cases versus controls and were considered in a larger sample of 1,363 patients and 1,251 control subjects. The relative risk of an individual with both p.G2385R and p.R1628P is about 1.9, and this is reduced to 1.5-1.6 if the individual also carries rs7133914:G>C; p.R1398H or rs7308720:C>A: p.N551K. The risk of a carrier with p.R1628P is largely negated if the individual also carries p.R1398H or p.N551K. In dopaminergic neuronal lines, p.R1398H had significantly lower kinase activity, whereas p.G2385R and p.R1628P showed higher kinase activity than wild type. We provided the first evidence that multiple LRRK2 variants exert an individual effect and together modulate the risk of PD among Chinese.

LRRK2 R1628P variant is a risk factor of Parkinson's disease among Han-Chinese from mainland China.

Mutations in LRRK2, the gene that encodes leucine-rich repeat kinase 2 (LRRK2), are associated with autosomal dominant and sporadic forms of Parkinson's disease (PD) and are the most common genetic causes of PD. Recently, a R1628P variant has been reported as a risk factor for PD in Taiwan and Singapore. To determine the association of this variant and PD in the Han-Chinese population from mainland China, we analyzed its frequency in a cohort of 600 patients and 459 unrelated healthy controls. Forty (6.7%) patients were heterozygous and 3 (0.5%) homozygous for the R1628P variant, which was significantly more frequent than in the controls [2.4% heterozygous and 0.0% homozygous, Odds ratio = 3.14, 95%CI: 1.60-6.17, P < 0.01]. Considering the age at onset, this difference was found only in late-onset PD (older than 50) [Odds ratio = 3.76, 95% CI: 1.90-7.45, P < 0.01]. Our data confirms that the LRRK2 R1628P variant is associated with an increased risk to develop late onset PD in the ethnic Han-Chinese population.

Meta-analysis of the influence of DRD3 Ser9Gly variant on susceptibility for essential tremor.

The dopamine D3 receptor (DRD3) Ser9Gly variant has attracted more attention since the variant was observed to be associated with risk of essential tremor (ET). A number of association studies concerning the DRD3 Ser9Gly variant and ET susceptibility have been conducted in various populations. However, some results were contradictory. To derive a more precise estimation of the relationship between the DRD3 Ser9Gly variant and the genetic risk of ET, we performed a comprehensive meta-analysis which included seven case-control studies. The meta-analysis was conducted in four genetic models: dominant, recessive, heterozygous, and homozygous. The odds ratio and 95% confidence intervals were used as the measure of association. The combined results of overall analysis showed a lack of association of the DRD3 Ser9Gly variant and ET, regardless of the genetic model of Ser9Gly. Publication bias and heterogeneity were absent in most analyses. In conclusion, the present meta-analysis does not support the notion that the DRD3 Ser9Gly variant is a genetic risk factor for ET.

Mutations in GBA and risk of Parkinson's disease: a meta-analysis based on 25 case-control studies.

The association between glucocerebrosidase (GBA) mutations and Parkinson's disease (PD) is attracting increased attention worldwide. Results from previous studies on the association of GBA mutations with PD in different ethnicities remain contradictory. In order to derive a more comprehensive understanding of the relationship between the most common GBA mutations, L444P and N370S and PD susceptibility, an updated meta-analysis was performed by searching PUBMED, EMBASE, MEDLINE, and EBSCO databases. Twenty five studies including 9, 599 cases and 13, 541 controls were collected in the end. The summary of odds ratios (OR) and corresponding 95% confidence intervals (CI) were estimated using fixed- and random-effects models, when appropriate. Overall, our meta-analysis provided evidence that both were risk factors associated with increased PD susceptibility. When stratified by ethnicities, the associations varied among different ethnical origins.

Genetic association study between STK39 and CCDC62/HIP1R and Parkinson's disease.

BACKGROUND: The first large-scale meta-analysis of published genome-wide association studies (GWAS) in Parkinson's disease (PD) identified 5 new genetic loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). Very recently, a large-scale replication and heterogeneity study also reported that STK39 and CCDC62/HIP1R increased risk of PD in Asian and Caucasian populations. However, their roles still remain unclear in a Han Chinese population from mainland China. METHODS: We examined genetic associations of STK39 rs2102808 and CCDC62/HIP1R rs12817488 with PD susceptibility in a Han Chinese population of 783 PD patients and 725 controls. We also performed further stratified analyses by the age of onset and accomplished in-depth clinical characteristics analyses between the different genotypes for each locus. RESULTS: No significant differences were observed in the minor allele frequency (MAF) among cases and controls at the two loci (STK39 rs2102808: OR = 1.06, 95% CI = 0.91, 1.23, P = 0.467; CCDC62/HIP1R rs12817488: OR = 0.88, 95% CI = 0.76, 1.01, P = 0.072). Subgroup analyses by the age of onset also showed no significant differences among different subgroups of the two loci. In addition, minor allele carriers cannot be distinguished from non-carriers based on their clinical features at the two loci. CONCLUSIONS: We are unable to demonstrate the association between STK39 and CCDC62/HIP1R and PD susceptibility in a Han Chinese population from mainland China. Additional replication studies in other populations and functional studies are warranted to better validate the role of the two new loci in PD risk.

Genetic analysis of LRRK2 A419V variant in ethnic Chinese.

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common causes of autosomal dominant and sporadic forms of Parkinson's disease (PD). The A419V variant has been suggested to be a potential risk variant but its role among Chinese is unclear. We genotyped LRRK2 A419V variant to investigate the association with risk of PD. A total of 1314 subjects comprising 729 patients with PD and 585 controls were genotyped. Twenty-two (3.0%) patients were heterozygous carriers for the A419V variant, and the frequency was higher compared with controls (0.7%, p = 0.003). The association was seen among the younger age group (early onset PD patients vs. controls: p = 0.0005), but was not significant among the older age group (late onset PD patients vs. controls: p = 0.17). We showed a significant association of LRRK2 A419V variant among early onset PD in the ethnic Han Chinese population but not among late onset PD. Further replication studies in additional Chinese and other Asian cohorts will be important to address its potential pathophysiologic role.

Functional parkin promoter polymorphism in Parkinson's disease: new data and meta-analysis.

BACKGROUND: A functional SNP (rs9347683) in the promoter region of the parkin gene had been implicated as a risk factor in older Parkinson's disease (PD) patients. METHODS: Using a case-control methodology, we genotyped the SNP in the promoter region of the parkin gene to investigate their association with risk of PD and conducted a pooled analysis of published papers in the English literature. RESULTS: A total of 1087 study subjects comprising 595 patients with PD and 492 unrelated healthy controls were recruited. The frequency of "GG" genotype in the elderly sub-group (≥ 65 years) was higher in PD compared to controls (OR=1.11) though we did not observe any difference in allele or genotype frequencies between the cases and the controls (P>0.05) in the overall PD population. Those with genotype "GG" were associated with a higher Hoehn-Yahr stage compared with PD patients carrying "GT"+"TT" (P=0.040). A pooled analysis involving more than >3000 subjects revealed that the frequency of genotypes in PD patients did not differ from the controls (OR=0.98, 95% CI: 0.86-1.12). However, in the group ≥ 65 years of age, the "GG" genotype was higher in PD (OR=1.51, 95% CI: 1.06-2.13, P=0.020) among the ethnic Chinese. CONCLUSIONS: While we did not demonstrate a significant association of the parkin promoter polymorphism with PD in our sample, the pooled data suggest that the variant may increase the risk of PD in the more elderly population among the ethnic Chinese, suggesting possible ethnicity-specific effect. Further in vitro and in vivo studies to evaluate this functional parkin variant are warranted.