SNCA variant associated with Parkinson disease and plasma alpha-synuclein level.
SNCA variant associated with Parkinson disease and plasma alpha-synuclein level.
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DOI：
10.1001/archneurol.2010.279
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发表时间：
2010-11
影响因子：
--
通讯作者：
Zabetian, Cyrus P.
中科院分区：
文献类型：
--
作者：
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.
SNCA启动子（REP 1）中的功能性重复多态性传递帕金森病（PD）的易感性。还有越来越多的证据表明，基因中其他地方的SNP与风险有关。我们试图进一步探索疾病相关性，确定是否存在等位基因异质性的证据，并检查PD相关变体与血浆α-突触核蛋白水平之间的相关性。我们使用全面的tagSNP方法对来自神经遗传学研究联盟的1，956名PD患者和2，112名对照进行了两层分析。还包括先前发表的REP 1基因型。采用高灵敏度的Luminex测定法测定了86例患者和78例对照者的血浆α-突触核蛋白。在第1层的加性模型下，15个基因分型的SNP中有5个与PD相关（α=0.05）。其中4个在第2层成功复制。在合并样本中，最显著的标记是rs356219（OR，1.41; CI，1.28-1.55; p = 1.6 × 10−12），位于基因下游约9 kb处。仅包含rs356219的回归模型最适合数据。该SNP与REP 1之间的连锁不平衡相关系数较低（r2=0.09）。rs356219的风险相关C等位基因在校正的相加模型下也与较高的转化血浆α-突触核蛋白水平相关（p = 0.005）。我们的数据表明，一个或多个未识别的功能SNCA变体改变PD的风险，并且其作用大于且独立于REP 1。该变体（由rs356219标记）可能通过以剂量依赖性方式上调SNCA表达而起作用。
A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson’s disease (PD). There is also increasing evidence that SNPs elsewhere in the gene associate with risk. We sought to further explore the disease association, determine whether evidence of allelic heterogeneity exists, and examine the correlation between PD-associated variants and plasma α-synuclein levels. We performed a two-tiered analysis of 1,956 PD patients and 2,112 controls from the NeuroGenetics Research Consortium using a comprehensive tagSNP approach. Previously published REP1 genotypes were also included. Plasma α-synuclein was assayed in 86 cases and 78 controls using a highly sensitive Luminex assay. Five of the 15 SNPs genotyped were associated with PD under an additive model in Tier 1 (α=0.05). Of these, four were successfully replicated in Tier 2. In the combined sample, the most significant marker was rs356219 (OR, 1.41; CI, 1.28–1.55; p = 1.6 × 10−12) located ~ 9 kb 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 (r2=0.09). The risk-associated C allele of rs356219 was also correlated with higher transformed plasma α-synuclein levels in cases under an adjusted additive model (p = 0.005). Our data suggest that one 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.
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影响因子：
30.8
作者：
Satake, Wataru;Nakabayashi, Yuko;Toda, Tatsushi
通讯作者：
Toda, Tatsushi
影响因子：
56.9
作者：
Singleton, AB;Farrer, M;Gwinn-Hardy, K
通讯作者：
Gwinn-Hardy, K
影响因子：
4.8
作者：
Fuchs, Julia;Tichopad, Ales;Gasser, Thomas
通讯作者：
Gasser, Thomas
影响因子：
3.5
作者：
Myhre, R.;Toft, M.;Farrer, M. J.
通讯作者：
Farrer, M. J.
DOI：
10.1073/pnas.0802437105
发表时间：
2008-08-05
影响因子：
11.1
作者：
Scherzer, Clemens R.;Grass, Jeffrey A.;Schlossmacher, Michael G.
通讯作者：
Schlossmacher, Michael G.