Maraganore Demetrius M, Lesnick Timothy G, Elbaz Alexis, Chartier-Harlin Marie-Christine, Gasser Thomas, Krüger Rejko, Hattori Nobutaka, Mellick George D, Quattrone Aldo, Satoh Jun-Ichi, Toda Tatsushi, Wang Jian, Ioannidis John P A, de Andrade Mariza, Rocca Walter A
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Ann Neurol. 2004 Apr;55(4):512-21. doi: 10.1002/ana.20017.
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.
泛素羧基末端水解酶L1（UCHL1）基因的S18Y变异与帕金森病（PD）之间已报道的负相关具有很强的生物学合理性。如果得到证实，该变异与PD的基因关联性可能支持将UCHL1基因及其产物作为PD治疗策略的分子靶点。鉴于此，我们对已发表的所有11项关于UCHL1 S18Y基因变异与PD的研究中的个体水平数据进行了联合汇总分析。共有1970例病例和2224例无关对照。我们发现S18Y与PD之间存在统计学上显著的负相关。变异等位基因携带者（Y/Y加Y/S与S/S相比）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与S/S加Y/S相比）的OR为0.71（95%CI，0.57 - 0.88）。对数OR呈线性趋势，与基因剂量效应一致（p = 0.01）。与年轻对照相比，这种负相关在年轻病例中最为明显。没有证据表明存在发表偏倚，排除首次发表的产生假设的研究后，这种关联性仍然显著。这些发现证实UCHL1是PD的一个易感基因，也是疾病修饰疗法的一个潜在靶点。
