UCHL1 is a Parkinson's disease susceptibility gene
UCHL1 is a Parkinson's disease susceptibility gene
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DOI：
10.1002/ana.20017
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发表时间：
2004-04-01
影响因子：
11.2
通讯作者：
Rocca, WA
中科院分区：
文献类型：
--
作者：
Maraganore, DM;Lesnick, TG;Rocca, WA
泛素羧基末端水解酶L1（UCHL 1）基因的S18 Y变异体与帕金森病（PD）之间的反向关联具有很强的生物学可解释性。如果得到证实，这种变异与PD的遗传关联可能支持UCHL 1基因及其产物的分子靶向作为PD的治疗策略。在这种情况下，我们对所有11项已发表的UCHL 1 S18 Y基因变异和PD研究的个体水平数据进行了协作汇总分析。有1，970例病例和2，224例无关对照。我们发现S18 Y与PD呈统计学显著负相关。变异等位基因携带者（Y/Y + Y/S vs S/S）的优势比（OR）为0.84（95%置信区间[CI]，0.73-0.95），变异等位基因纯合子（Y/Y vs S/S + Y/S）的OR为0.71（95% CI，0.57-0.88）。log OR呈线性趋势，与基因剂量效应一致（p = 0.01）。与年轻对照组相比，年轻病例的负相关性最明显。没有证据表明存在发表偏倚，排除第一个发表的假设研究后，相关性仍然显著。这些发现证实了UCHL 1是PD的易感基因，也是疾病修饰疗法的潜在靶点。
The reported inverse association between the S18Y variant of the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene and Parkinson's disease (PD) has strong biological plausibility. If confirmed, genetic association of this variant with PD may support molecular targeting of the UCHL1 gene and its product as a therapeutic strategy for PD. In this light, we performed a collaborative pooled analysis of individual-level data from all 11 published studies of the UCHL1 S18Y gene variant and PD. There were 1,970 cases and 2,224 unrelated controls. We found a statistically significant inverse association of S18Y with PD. Carriers of the variant allele (Y/Y plus Y/S vs S/S) had an odds ratio (OR) of 0.84 (95% confidence interval [CI], 0.73-0.95) and homozygotes for the variant allele (Y/Y vs S/S plus Y/S) had an OR of 0.71 (95% CI, 0.57-0.88). There was a linear trend in the log OR consistent with a gene dose effect (p = 0.01). The inverse association was most apparent for young cases compared with young controls. There was no evidence for publication bias and the associations remained significant after excluding the first published, hypothesis-generating study. These findings confirm that UCHL1 is a susceptibility gene for PD and a potential target for disease-modifying therapies.