Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease
Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease
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DOI：
10.1001/jama.296.6.661
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发表时间：
2006-08-09
影响因子：
120.7
通讯作者：
Van Broeckhoven, Christine
中科院分区：
文献类型：
--
作者：
Maraganore, Demetrius M.;de Andrade, Mariza;Van Broeckhoven, Christine
背景帕金森病易感基因在人群水平上的识别和复制受到具有潜在偏倚的小型研究的阻碍。目的探讨SNCA基因启动子区二核苷酸重复序列（REP 1）的等位基因长度变异与帕金森病易感性的关系，SNCA基因启动子区单倍型与帕金森病的关系，以及REP 1变异是否改变帕金森病的发病年龄。我们对帕金森病患者和对照组的SNCA REP 1和侧翼标记物的个体水平数据进行了合作分析。在2004年4月5日至2005年12月31日期间进行了研究中心招募、数据收集和分析。全球遗传学联盟的18个参与研究中心提供了临床数据。基因分型进行SNCA REP 1，-770，和-116标记在个别网站，但是，每个网站还提供了20个DNA样本的regenotyping centralized.Main Outcome Measures措施包括估计的Hardy-Weinberg平衡控制;异质性测试;分析关联的单一变异或单倍型;和生存分析的发病年龄。结果18个位点中，11个位点符合Hardy-Weinberg平衡，基因分型错误率低。这11个研究中心提供了2692例病例和2652例对照的完整数据。研究间无异质性（P > 0.60）。SNCA REP 1等位基因在病例组和对照组中的频率不同（P <0.001）。由263个碱基对等位基因定义的基因型与帕金森病相关（优势比，1.43; 95%置信区间，1.22-1.69;趋势P <0.001）。多位点单倍型在病例组和对照组中的频率不同（总体得分统计，P <0.001）。只有当两个基因座的单倍型中包括REP 1时，它们才与帕金森病相关。然而，REP 1等位基因定义的基因型并没有改变发病年龄（P = .55）。结论这种大规模的协作分析表明，SNCA REP 1等位基因长度变异与帕金森病的风险增加。
Context Identification and replication of susceptibility genes for Parkinson disease at the population level have been hampered by small studies with potential biases. alpha-Synuclein (SNCA) has been one of the most promising susceptibility genes, but largescale studies have been lacking.Objective To determine whether allele-length variability in the dinucleotide repeat sequence (REP1) of the SNCA gene promoter is associated with Parkinson disease susceptibility, whether SNCA promoter haplotypes are associated with Parkinson disease, and whether REP1 variability modifies age at onset.Design, Setting, and Participants We performed a collaborative analysis of individual-level data on SNCA REP1 and flanking markers in patients with Parkinson disease and controls. Study site recruitment, data collection, and analyses were performed between April 5, 2004, and December 31, 2005. Eighteen participating sites of a global genetics consortium provided clinical data. Genotyping was performed for SNCA REP1, -770, and -116 markers at individual sites; however, each site also provided 20 DNA samples for regenotyping centrally.Main Outcome Measures Measures included estimations of Hardy-Weinberg equilibrium in controls; a test of heterogeneity; analyses for association of single variants or haplotypes; and survival analyses for age at onset. Results Of the 18 sites, 11 met stringent criteria for concordance with Hardy-Weinberg equilibrium and low genotyping error rate. These 11 sites provided complete data for 2692 cases and 2652 controls. There was no heterogeneity across studies (P > .60). The SNCA REP1 alleles differed in frequency for cases and controls (P < .001). Genotypes defined by the 263 base-pair allele were associated with Parkinson disease (odds ratio, 1.43; 95% confidence interval, 1.22-1.69; P < .001 for trend). Multilocus haplotypes differed in frequency for cases and controls (global score statistic, P < .001). Two- loci haplotypes were associated with Parkinson disease only when they included REP1 as one of the loci. However, genotypes defined by REP1 alleles did not modify age at onset (P = .55).Conclusion This large-scale collaborative analysis demonstrates that SNCA REP1 allele-length variability is associated with an increased risk of Parkinson disease.