SNP rs356219 of the α-synuclein (SNCA) gene is associated with Parkinson's disease in a Chinese Han population

BackgroundOver the last decades, increasing knowledge about the genetic architecture of Parkinson’s disease(PD) has provided novel insights into the pathogenesis of the disorder. Recently, several studies in different populations have found a strong association between idiopathic PD and the single-nucleotide polymorphism (SNP) rs356219, which is located in the 3′UTR of the SNCA gene. In this study, we aimed to verify these findings and to explore further the nature of the association in a subset of Chinese Han PD patients.MethodsFour hundred and three unrelated patients with sporadic PD and 315 healthy ethnically matched control subjects were recruited consecutively for the study. Patients and normal controls were genotyped for SNCA rs356219 variant by ligase detection reaction (LDR).ResultsA statistically significant difference was found in the frequencies of the single alleles of rs356219 (χ² = 12.986,P = 0.002) between PD patients and normal subjects. The distribution of A > G genotypes was different between patients and controls (χ² = 13.243, P < 0.001). The OR for subjects with the variant genotypes (AG and GG) was 1.88 (95%CI = 1.27–2.78, P = 0.001). The frequencies of the homozygous genotype for this variant was 42.2% (170 patients), which was significantly higher than that in controls (32.4%, P < 0.001).ConclusionThe results suggested that SNCA rs356219 variant might have an increased risk of susceptibility to PD in a Chinese Han population. Further studies are needed to replicate the association that we found.     

A Search for SNCA 3′ UTR Variants Identified SNP rs356165 as a Determinant of Disease Risk and Onset Age in Parkinson’s Disease

Alpha-synuclein gene (SNCA) polymorphisms have been associated with the common sporadic form of Parkinson's disease (PD). We searched for DNA variants at the SNCA 3' UTR through single strand conformation analysis and direct sequencing in a cohort of Spanish PD patients and controls. We have genotyped the rs356165 SNCA 3' UTR polymorphism in a total of 1,135 PD patients and 772 healthy controls from two Spanish cohorts (Asturias and Navarre). We identified six SNCA 3' UTR variants. Single nucleotide polymorphism (SNP) rs356165 was significantly associated with PD risk in the Spanish cohort (p?=?0.0001; odd ratio?=?1.37, 95%CI?=?1.19-1.58). This SNP was also significantly associated with early age at onset of PD. Our work highlights rs356165 as an important determinant of the risk of developing PD and early age at onset and encourages future research to identify a functional effect on SNCA expression.     

SNCA,MAPT, and GSK3B in Parkinson disease: a gene–gene interaction study

Background and purpose: Recent evidence suggests that variation in the SNCA, MAPT, and GSK3B genes interacts in affecting risk for Parkinson disease (PD). In the current study, we attempt to validate previously published findings, evaluating gene–gene interactions between SNCA, MAPT, and GSK3B in association with PD. Methods: Three Caucasian PD patient–control series from the United States, Ireland, and Norway (combined n = 1020 patients and 1095 controls) were genotyped for SNCA rs356219, MAPT H1/H2‐discriminating SNP rs1052553, and GSK3B rs334558 and rs6438552. Results: Our findings indicate that as previously reported, the SNCA rs356219‐G allele and MAPT rs1052553 (H1 haplotype) were both associated with an increased risk of PD, whilst contrary to previous reports, GSK3B variants were not. No pair‐wise interaction was observed between SNCA, MAPT, and GSK3B; the risk effects of SNCA rs356219‐G and MAPT rs1052553‐H1 were seen in a similar manner across genotypes of other variants, with no evidence suggesting synergistic, antagonistic, or deferential effects. Conclusions: In the Caucasian patient–control series examined, risk for PD was influenced by variation in SNCA and MAPT but not GSK3B. Additionally, those three genes did not interact in determining disease risk.     

α-突触核蛋白基因多态性与汉族帕金森病患者病情进展的相关性研究

目的探讨α-突触核蛋白基因rs11931074位点多态性与帕金森病患者病情进展的相关性。方法采用病例对照研究方法,选取2014年3月至2017年10月在南京脑科医院就诊的帕金森病患者154例(PD组)及健康体检志愿者194例(对照组)为研究对象,采用MassARRAY■SNP方法对SNCA基因rs11931074位点多态性进行分析,分别在患者基线及随访(3年)时间点进行UPDRS、HAMD、HAMA、PDNMSQ、PDSS、MMSE等相关量表评估,计算差值年限比(即基线及随访时差值/年限),分析基因rs11931074多态性与帕金森病病情进展的相关性。结果与对照组比较,PD组rs11931074T等位基因、TT基因型变异频率高干对照组(P=0.01);线性相关分析示rs11931074变异(GT+TT)携带者发病年龄越大,日常生活能力损害越严重(P=0.03);多因素线性回归分析示SNCA基因rs11931074位点与PD患者强直症状进展相关(P=0.036);SNCA基因rs11931074TT基因型与PD患者强直症状进展相关(P=0.03)。结论SNCA基因rs11931074位点多态性与帕金森病病情进展相关;rs11931074 TT基因型与帕金森病强直症状进展相关,随着病程进展基因rs11931074变异(GT+TT)携带者日常生活能力损害更严重。     

<Emphasis Type="Italic">TOX3</Emphasis> Variants Are Involved in Restless Legs Syndrome and Parkinson’s Disease with Opposite Effects

Parkinson’s disease (PD) and restless legs syndrome (RLS) may be clinically and/or etiologically related, yet this association is under debate. Single-nucleotide polymorphisms (SNPs) in the TOX3 gene locus were implicated in both RLS and PD genome-wide association studies (GWASs), suggesting a potential pleiotropy. Two case-control cohorts including 644 PD patients, 457 RLS patients, and 945 controls were genotyped for one known RLS-related SNP (rs3104767) and one PD-related SNP (rs4784226) in the TOX3 locus. The associations between genotype and PD and RLS risk were tested using multivariate regression models. The allele frequencies of RLS-related SNP rs3104767 in RLS patients and controls were 0.35 and 0.43, respectively (OR 0.70, p?=?0.0007). Regression model suggested that this association is derived by homozygous carriage of rs3104767 (adjusted p?=?0.008). A nominal association was observed for homozygous carriers of the rs3104767 SNP in PD (OR 1.62, 95% CI 1.05–2.54, p?=?0.034), i.e., with an opposite direction of effect on RLS and PD, but this was not significant after Bonferroni correction. However, data from published GWASs of RLS and PD, and from the PDgene database, further supported these inverse associations. Our results confirm the association between the TOX3 SNP rs3104767 and RLS and suggest that TOX3 variants are involved in both RLS and PD, but with different or even opposite effects. Studies in larger populations of different ethnicities are required to further refine the TOX3 locus is involved in RLS and PD.     

Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease

OBJECTIVE: Parkinson's disease (PD) is a neurodegenerative condition that typically presents as a movement disorder but is known to be associated with variable degrees of cognitive impairment including dementia. We investigated the genetic basis of susceptibility to and cognitive heterogeneity of this disease. METHODS: In 659 PD patients, 109 of which were followed up for 3.5 years from diagnosis, and 2,176 control subjects, we studied candidate genes involved in protein aggregation and inclusion body formation, the pathological hallmark of parkinsonism: microtubule-associated protein tau (MAPT), glycogen synthase kinase-3beta (GSK3B), and alpha-synuclein (SNCA). RESULTS: We observed that cognitive decline and the development of PD dementia are strongly associated (p = 10(-4)) with the inversion polymorphism containing MAPT. We also found a novel synergistic interaction between the MAPT inversion polymorphism and the single nucleotide polymorphism rs356219 from the 3' region of SNCA. In our data, carrying a risk genotype at either of these loci marginally increases the risk for development of PD, whereas carrying the combination of risk genotypes at both loci approximately doubles the risk for development of the disease (p = 3 x 10(-6)). INTERPRETATION: Our data support the hypothesis that tau and alpha-synuclein are involved in shared or converging pathways in the pathogenesis of PD, and suggest that the tau inversion influences the development of cognitive impairment and dementia in patients with idiopathic PD. These findings have potentially important implications for understanding the interface between tau and alpha-synuclein pathways in neurodegenerative disorders and for unraveling the biological basis for cognitive impairment and dementia in PD.     

Association of VEGF gene polymorphisms with sporadic Parkinson’s disease in Chinese Han population

Recent evidence indicates that vascular endothelial growth factor (VEGF) is capable of protecting dopaminergic (DA) neurons. Parkinson’s disease (PD) is a progressive neurodegenerative disease caused by the degeneration of nigrostriatal dopaminergic neurons. To evaluate the role of VEGF single nucleotide polymorphisms (SNPs) and haplotypes in PD, we performed a case–control study including 400 PD patients and 400 healthy-matched controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) analysis and DNA sequencing were used to detect the rs699947, rs2010963 and rs3025039 polymorphisms of the VEGF gene in cases and controls. Our study revealed that T allelic frequency of rs3025039 polymorphism was significantly higher in PD subjects (OR 1.497, 95 % CI 1.099–2.040, P = 0.013) than that in controls. Significant association for rs3025039 could be found in additive model (TT vs. CT vs. CC: OR 1.489, 95 % CI 1.018–2.177, P = 0.040) and dominant model (TT + CT vs. CC: OR 1.538, 95 % CI 1.068–2.216, P = 0.021). Subgroup analyses performed by gender suggested that this association could be found in male, but not in female. Moreover, it also demonstrated a significant association in the subgroup of late-onset PD (LOPD). However, for rs699947 and rs2010963 polymorphisms, genotype or allele frequencies did not differ between groups. No significant association could be found between rs699947 and rs2010963 polymorphism and PD risk. None of the observed haplotypes showed significant association with PD. Therefore, these results suggested that the VEGF gene might be associated with risk of developing sporadic PD in Han Chinese and the rs3025039 polymorphism may be a risk factor for sporadic PD.     

Age at Onset in LRRK2-Associated PD is Modified by SNCA Variants

Mutations in the leucine-rich repeat kinase 2 (LRRK2) and α-synuclein (SNCA) genes are known genetic causes of Parkinson's disease (PD). Recently, a genetic variant in SNCA has been associated with a lower age at onset in idiopathic PD (IPD). We genotyped the SNCA polymorphism rs356219 in 84 LRRK2-associated PD patients carrying the G2019S mutation. We found that a SNCA genetic variant is associated with an earlier age at onset in LRRK2-associated PD. Our results support the notion that SNCA variants can modify the pathogenic effect of LRRK2 mutations as described previously for IPD.     

Association between PLA2G6 gene polymorphisms and Parkinson's disease in the Chinese Han population

The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A(2), and has been suggested as the causative gene for autosomal recessive dystonia-parkinsonism. We conducted a case-control study using 531 mainland Chinese Parkinson's disease (PD) patients and 561 healthy controls, and genotyped 4 tag single nucleotide polymorphisms (SNPs) of the PLA2G6 gene: rs4375, rs2267369, rs132985, and rs2284063. Logistic regression analysis revealed no difference in genotype or allele frequencies for any of the SNPs between the sporadic PD group and control group. Similarly, comparison of SNPs in patients with either early-onset (EOPD, ≤ 50 years) or late-onset (>50 years) PD revealed no statistical differences from controls. We detected no significant association of the 4 SNPs with PD at the genotypic level, after adjustment for age. The rs132985 genotype frequency showed a difference in male patients but not in female patients, but the P value did not survive Bonferroni correction (Pcorr = 0.068). We found that the rs132985 A-rs2284063 C haplotype is marginally associated with increased risk of developing PD (P = 0.048) after 10,000 permutations. These findings suggest that PLA2G6 is not a susceptibility gene for PD in our population. However, a broader examination and a replication of this study in other populations are needed.     

Impact of CRP gene and additional gene–smoking interaction on ischemic stroke in a Chinese Han population

Aims: To investigate the association of C-reactive protein (CRP) gene single nucleotide polymorphisms (SNPs), additional gene–gene, and gene–smoking interaction with ischemic stroke (IS) risk.

Methods: Logistic regression is performed to investigate association between SNPs within CRP gene and IS risk. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene–gene and gene–smoking interaction, cross-validation consistency, the testing balanced accuracy and the sign test were calculated.

Results: Logistic analysis showed that three SNPs were all associated with decreased IS risk in additive and dominant models. The IS risks were lower in carriers of homozygous mutant of rs2794521 polymorphism and heterozygous of rs3093059 and rs1205 than those with wild-type homozygotes genotype, OR (95%CI) were 0.62 (0.40–0.90), 0.68 (0.50–0.96) and 0.65 (0.46–0.97), respectively. GMDR analysis suggested a significant two-locus model (P = 0.0010) involving rs2794521 and rs3093059. We also found a significant two-locus model (P = 0.0010) involving rs2794521 and smoking. Participants with rs2794521-AG or GG and rs3093059-AG or GG genotype have the lowest IS risk, compared to participants with rs2794521-AA and rs3093059-AA genotype, OR (95%CI) was 0.4 2 (0.233–0.61). In addition, non-smokers with rs2794521-AG or GG genotype have the lowest IS risk, compared to smokers with rs2794521-AA genotype, OR (95%CI) was 0.47 (0.23–0.76).

Conclusions: We found that rs2794521, rs3093059, and rs1205 were associated with decreased IS risk; we also found that gene–gene interaction between rs2794521 and rs3093059, and gene–environment interaction between rs2794521 and smoking were associated with decreased IS risk.     

SNCA: Major genetic modifier of age at onset of Parkinson's disease

Age at onset serves as a predictor of progression and mortality in sporadic Parkinson's disease (PD). Therefore, the identification of genetic modifiers for age at onset might lead to a better understanding of disease pathogenesis. We performed multivariate linear regression analysis in 1396 sporadic PD patients assessing 21 single‐nucleotide polymorphisms (SNPs) that have been previously suggested to be associated with sporadic PD. Moreover, a cumulative risk score was assigned to each patient and correlated with age at onset. We identified the rs356219 risk allele in the SNCA gene as significantly contributing to earlier age at onset. Neither one of the other 21 SNPs tested in this analysis nor the cumulative number of risk alleles showed a significant impact on PD onset. Because sequence variants in the SNCA gene are not only associated with autosomal dominantly inherited PD and increased susceptibility for sporadic PD but also have been found to modify the phenotype such as age at onset in both sporadic and various monogenic forms of PD, this gene serves as an outstanding target for further research on PD pathogenesis, which in return might provide potential therapeutic options. © 2013 Movement Disorder Society     

Interactions between four gene polymorphisms and their association with patients with Parkinson's disease in a Chinese Han population

The four previously reported Parkinson's disease (PD)-related single-nucleotide polymorphisms (SNPs) – rs1775143, rs823114, rs2071746 and rs62063857 – have rarely been studied in Chinese Han populations. To examine the association between these SNPs and PD, we conducted a case-control study of 158 patients with PD and 210 controls. All participants were Chinese Han from Northern China. With covariate adjustment for clinical characteristics, logistic regression analysis revealed no differences in genotype or allele frequencies for the four SNPs. Stratified by age of disease onset, sex, smoking status, duration of disease, baseline UPDRS, Hoehn–Yahr Stage, PD subtypes, scores of Hamilton anxiety scale, Hamilton depression scale and activity of daily living, all of the p values did not remain significant after Bonferroni correction. However, the haplotype rs1775143T-rs823114G-rs2071746T-rs62063857A was associated with increased risk of developing PD (p = 0.003, OR = 456.88, 95% CI: 27.40–7619.75) in our case-control sample set. The haplotype rs1775143T-rs823114G-rs2071746T was also associated with increased risk of developing PD (p = 0.003, OR = 338.43, 95% CI: 20.68–5538.27). Although the haplotype rs1775143T-rs823114G-rs62063857A was associated with increased risk of PD (p = 0.03), the 95% CI was 0.993–22.469. Our data demonstrate that although specific SNPs were not related with PD patients, certain haplotypes were associated with increased risk for PD in the Chinese Han population. These results provide further evidence that the etiology of PD is multifactorial, although the underling mechanism needs further study.     

Two Novel SNPs in the PLCL2 Gene Associated with Large Artery Atherosclerotic Stroke Identified by Fine-Mapping

A genome-wide association study (GWAS) reported that the single nucleotide polymorphism (SNP) rs4618210 in the PLCL2 gene is related to myocardial infarction (MI) in the Japanese population, but no study has examined the correlation of PLCL2 with ischemic stroke (IS). The present study was designed to investigate whether the genetic variation in PLCL2 is associated with large artery atherosclerotic (LAA) stroke in a Han Chinese population. Tagging SNPs (tSNPs) of the PLCL2 gene were determined by a fine-mapping strategy and were genotyped by improved multiplex ligation detection reaction (iMLDR) technology in 669 LAA stroke patients and 668 healthy controls. A logistic regression model was used to analyze the associations between genetic variation at PLCL2 and the risk of LAA stroke. Two SNPs were significantly associated with the risk of LAA stroke after adjusting for potential confounders: for rs4685423, the AA genotype and CA genotype decreased the risk of LAA stroke compared with the CC genotype (multivariate-adjusted, P = 0.001); for rs4618210, the AA genotype and GA genotype decreased the risk of LAA stroke compared with the GG genotype (multivariate-adjusted, P = 0.007). In addition, haplotype analysis indicated that compared with haplotype TTT, haplotype TAT decreased the risk of LAA stroke in block 2 (adjusted OR, 0.706; 95% CI, 0.550–0.907; P = 0.006). The analysis of SNP–SNP interactions showed that rs4685423 was the most influential contributor to LAA stroke risk. SNPs rs4685423 and rs4618210 in the PLCL2 gene may be related to the risk of LAA stroke in Han Chinese.     

Variant in the 3′ region of SNCA associated with Parkinson’s disease and serum α-synuclein levels

Parkinson's disease (PD) is the second most common neurodegenerative disorder. The presence of Lewy bodies is a major pathological change of PD. α-synuclein is the main component of Lewy bodies and is encoded by the SNCA gene. Mutations in the SNCA gene mainly result in rare familial forms of PD, while genetic variability in the SNCA gene modulates susceptibility to sporadic PD. Recent studies have suggested that levels of α-synuclein in extracellular biological fluid are associated with PD and implicated α-synuclein as a potential biomarker for PD diagnosis and severity. We studied serum α-synuclein concentration and two polymorphic variants of SNCA (Rep1 and rs11931074) in 110 sporadic PD patients and 136 controls. We further explored the influence of the two polymorphisms on the expression levels of serum α-synuclein. Soluble α-synuclein was detected in serum in all subjects, with no statistically significant difference between PD patients and controls (p?=?0.611). Different Rep1 alleles and genotypes did not influence the expression of serum α-synuclein. The frequency of allele T of rs11931074 was significantly elevated in PD patients (p?=?0.041), and was correlated with decreased serum α-synuclein in both dominant (p?=?0.011) and additive (p?=?0.008) models of association.     

DVL2基因多态性与中国汉族人群先天性脊柱侧凸遗传易感性的关联研究*☆◇

背景：近20年来小鼠的分子胚胎学研究进展获得了大量关于脊椎发育的分子信息,用同线性分析法确立先天性脊柱侧凸的候选基因已成为可能。 目的：通过候选基因DVL2上关键单核苷酸多态性位点的筛查,探索DVL2与中国汉族人群先天性脊柱侧凸及其不同临床表型之间的关联。 方法：采用病例-对照研究,入选127例中国汉族先天性脊柱侧凸患者和127例对照组。根据国际人类基因组单体型图计划提供的基因型数据,应用Haploview 4.1软件选取DVL2的标签和功能单核苷酸多态性。根据椎体畸形特点、畸形部位、畸形受累程度、有无合并肋骨畸形和椎管内畸形将病例组进一步分为不同临床表型。对所有样本应用SNPstream UHT Genotyping系统对所选单核苷酸多态性位点进行基因型鉴定;进一步进行基于基因型/等位基因频率的关联分析,并用Haploview 4.1软件分析对照组单核苷酸多态性位点间是否存在连锁不平衡。 结果与结论：共筛选5个位点：单核苷酸多态性1(rs2074222)、单核苷酸多态性2(rs222837)、单核苷酸多态性3(rs222835)、单核苷酸多态性4(rs10671352)和单核苷酸多态性5(rs222836),其基因型分布在病例和对照组中均符合Hardy-Weinberg平衡;5个位点处于完全连锁不平衡状态;5个位点的基因型/等位基因/单倍体型与先天性脊柱侧凸的发生风险之间不存在相关性。在进一步与先天性脊柱侧凸临床表型的关联分析中没有发现阳性位点。提示在中国汉族人群中DVL2基因可能不是引起先天性脊柱侧凸及其不同临床表型的主要因素,有待于进一步深入研究。     

SORL1基因多态性与中国东北地区帕金森病的相关性分析

目的探究SORL1基因rs2070045位点的单核苷酸多态性与帕金森病(Parkinson disease,PD)的相关性。方法本研究纳入215名中国东北地区汉族健康人和377例PD患者。根据其发病年龄,将PD组患者再分为早发PD组(发病年龄≤50岁)和晚发PD组(发病年龄50岁),收集一般临床资料,提取外周血基因组DNA,利用MALDI-TOF-PEX技术检测SORL1基因rs2070045多态性分布情况,分析其与帕金森病的相关性。结果在PD组与对照组以及晚发PD组与对照组的比较中,SORL1基因rs2070045位点单核苷酸多态性的基因型及等位基因频率分布无统计学差异。早发PD组与对照组比较,rs2070045基因型分布有显著差异(P=0.036),而等位基因频率无显著差异。在晚发PD中G等位基因携带者的起病年龄明显低于非携带者(P=0.001),其他临床特征如性别、Hoehn-Yahr分期以及病程在携带者和非携带者间无统计学差异。结论 SORL1基因rs2070045位点的单核苷酸多态性与中国东北地区汉族早发帕金森病相关,G等位基因可能是早发PD的保护性因素。     

Extended evidence for association between the melanoma inhibitory activity 3 gene and myocardial infarction

In a genome-wide scan, isolated single nucleotide polymorphisms (SNPs), including rs17465637, in the melanoma inhibitory activity 3 gene (MIA3) on chromosome 1 were identified to be associated with coronary artery disease and myocardial infarction (MI). Because the role of common variation at the MIA3 locus has not yet been investigated, the aim of this case-control study was to determine the impact of haplotype-tagging SNPs and haplotypes in the MIA3 region on the risk of MI. In a set of nine haplotype-tagging SNPs, rs17465637, but none of the other SNPs, was associated with MI. After adjustments were made for age, gender, history of arterial hypertension, history of hypercholesterolaemia, current cigarette smoking and diabetes mellitus, multiple logistic regression analyses showed an increased risk in the carriers of one or two C alleles [adjusted odds ratio (OR) 1.17, 95% confidence interval (CI) 1.04-1.32, and 1.37, 95% CI 1.08-1.74, respectively]. Nine common haplotypes (frequency >1%) were established across the MIA3 region. Two of the haplotypes were associated with an increased risk of MI: the frequent (48%) TGACCAAAG haplotype and the rare (2%) CGACCAAAG haplotype (adjusted OR 1.102, 95% CI 1.002-1.212, and 1.574, 95% CI 1.077-2.298, respectively). Showing association between rs17465637 and MI, this work was consistent with results from the original detection study and most prior replication studies addressing this issue. In addition to correspond with such isolated evidence of association with MI, the present study identified specific haplotypes capturing the risk-related variation in the entire MIA3 region.     

Genetic variants of SNCA and LRRK2 genes are associated with sporadic PD susceptibility: A replication study in a Taiwanese cohort

BackgroundParkinson's disease (PD) is one of the most prevalent age-related neurodegenerative diseases and usually refers to a complex disorder with multiple genetic and environmental factors influencing disease risk. We here performed a gene-based case–control association study to scrutinize whether genetic variants in SNCA and LRRK2 genes could predispose to sporadic, late-onset form of PD in Taiwanese population.Methods17 Single Nucleotide Polymorphisms (SNPs) markers located within SNCA gene as well as the 16 SNP markers within LRRK2 gene were chosen for genotyping and evaluated their haplotype structure in a cohort of sporadic PD patients and control individuals.ResultsThis study showed that two SNPs near the promoter region (rs2301134 and rs2301135) of SNCA gene gave the greatest evidence for an association with PD (p ≤ 0.01) and a haplotype block with two SNPs in the 3′ UTR (rs356221 and rs11931074) revealed another evidence of association (p ≤ 0.02). For the LRRK2 gene, only R1628P variants of total 16 SNPs giving a marginal significant association with PD across the whole gene (p = 0.0058) and no haplotype block was constructed. Many genetic variants (A419V, I1122V, R1441C, R1441G, R1441H, Y1699C, M1869 V, M1869T, I2012T, G2019S, and I2020T) from previous reports were not detected in our cohort.ConclusionsWe have replicated a population-based PD association study in a collection of 626 cases and 473 control subjects and confirm that genetic variants of both SNCA and LRRK2 genes are associated with susceptibility to sporadic PD but in a different distribution.     

NOS2A and the modulating effect of cigarette smoking in Parkinson's disease

OBJECTIVE: Inducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. NOS2A is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined NOS2A for association with PD risk and age at onset (AAO) and for interaction with smoking. METHODS: We genotyped 13 NOS2A single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations. RESULTS: Among the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (p = 0.000059 and 0.0062, respectively) and genotypic (p = 0.0039 and 0.0014, respectively) associations with risk and AAO (p = 0.00070 and 0.0073, respectively); the two-SNP haplotype generated even stronger association with PD (p = 0.000013). Significant interactions with smoking (p = 0.0015 for rs 2255929 and p < 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers. INTERPRETATION: Our findings support NOS2A as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking.