Mata Ignacio F, Shi Min, Agarwal Pinky, Chung Kathryn A, Edwards Karen L, Factor Stewart A, Galasko Douglas R, Ginghina Carmen, Griffith Alida, Higgins Donald S, Kay Denise M, Kim Hojoong, Leverenz James B, Quinn Joseph F, Roberts John W, Samii Ali, Snapinn Katherine W, Tsuang Debby W, Yearout Dora, Zhang Jing, Payami Haydeh, Zabetian Cyrus P
Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Mailstop S-182, 1660 S Columbian Way, Seattle, WA 98108, USA.
Arch Neurol. 2010 Nov;67(11):1350-6. doi: 10.1001/archneurol.2010.279.
A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson disease (PD). There is also increasing evidence that single-nucleotide polymorphisms (SNPs) elsewhere in the gene are associated with PD risk.
To further explore the association of common SNCA SNPs with PD susceptibility, to determine whether evidence of allelic heterogeneity exists, and to examine the correlation between PD-associated variants and plasma α-synuclein levels.
Two-tiered analysis.
Academic research.
Patients and control subjects from the NeuroGenetics Research Consortium.
We performed a 2-tiered analysis of 1956 patients with PD and 2112 controls from the NeuroGenetics Research Consortium using a comprehensive tag SNP approach. Previously published REP1 genotypes were also included. Plasma α-synuclein was assayed in 86 patients with PD and 78 controls using a highly sensitive Luminex assay.
Five of 15 SNPs genotyped were associated with PD under an additive model in tier 1 (α = .05). Of these, 4 were successfully replicated in tier 2. In the combined sample, the most significant marker was rs356219 (odds ratio, 1.41; 95% confidence interval, 1.28-1.55; P = 1.6 × 10(-12)), located approximately 9 kilobases downstream from the gene. A regression model containing rs356219 alone best fit the data. The linkage disequilibrium correlation coefficient between this SNP and REP1 was low (r(2) = 0.09). The risk-associated C allele of rs356219 was also correlated with higher transformed plasma α-synuclein levels in patients under an adjusted additive model (P = .005).
Our data suggest that 1 or more unidentified functional SNCA variants modify risk for PD and that the effect is larger than and independent of REP1. This variant(s), tagged by rs356219, might act by upregulating SNCA expression in a dose-dependent manner.
α-突触核蛋白基因（SNCA）启动子区的一个功能性重复多态性（REP1）与帕金森病（PD）易感性相关。越来越多的证据表明，该基因其他位置的单核苷酸多态性（SNP）也与PD风险相关。
进一步探讨常见SNCA SNP与PD易感性的关联，确定是否存在等位基因异质性证据，并研究PD相关变异与血浆α-突触核蛋白水平之间的相关性。
两级分析。
学术研究机构。
神经遗传学研究联盟的患者和对照者。
我们采用综合标签SNP方法，对神经遗传学研究联盟的1956例PD患者和2112例对照者进行了两级分析。还纳入了先前发表的REP1基因型。使用高灵敏度的Luminex检测法对86例PD患者和78例对照者的血浆α-突触核蛋白进行了检测。
在一级分析中，15个基因分型的SNP中有5个在加性模型下与PD相关（α = 0.05）。其中，4个在二级分析中成功复制。在合并样本中，最显著的标记是rs356219（优势比，1.41；95%置信区间，1.28 - 1.55；P = 1.6 × 10⁻¹²），位于该基因下游约9千碱基处。仅包含rs356219的回归模型最符合数据。该SNP与REP1之间的连锁不平衡相关系数较低（r² = 0.09）。在调整后的加性模型下，rs356219的风险相关C等位基因也与患者血浆α-突触核蛋白水平升高相关（P = 0.005）。
我们的数据表明，1个或更多未确定的功能性SNCA变异会改变PD风险，且其作用大于REP1且独立于REP1。由rs356219标记的该变异可能通过以剂量依赖方式上调SNCA表达而起作用。
