Clark L N, Ross B M, Wang Y, Mejia-Santana H, Harris J, Louis E D, Cote L J, Andrews H, Fahn S, Waters C, Ford B, Frucht S, Ottman R, Marder K
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Neurology. 2007 Sep 18;69(12):1270-7. doi: 10.1212/01.wnl.0000276989.17578.02.
To evaluate the frequency of glucocerebrosidase (GBA) mutations in cases and controls enrolled in the Genetic Epidemiology of Parkinson's Disease (GEPD) study.
We sequenced all exons of the GBA gene in 278 Parkinson disease (PD) cases and 179 controls enrolled in GEPD, with a wide range of age at onset (AAO), and that included a subset of 178 Jewish cases and 85 Jewish controls. Cases and controls were recruited without knowledge of family history of PD, and cases were oversampled in the AAO < 50 years category.
13.7% of PD cases (38/278) carried GBA mutations, compared with 4.5% of controls (8/179) (odds ratio [OR] 3.4, 95% CI 1.5 to 7.4). The frequency of GBA mutations was 22.2% in 90 cases with AAO < or = 50 years, compared with 9.7% in 185 cases with AAO > 50 years (OR 2.7, 95% CI 1.3 to 5.3). Adjusting for age at the time of evaluation, sex, family history of PD, and Jewish ancestry, GBA carriers had a 1.7-year-earlier AAO of PD (95% CI 0.5 to 3.3, p < 0.04) than noncarriers. The average AAO of PD was 2.5 years earlier in carriers with an AAO < or = 50 years compared with noncarriers (95% CI 0.6 to 4.5, p < 0.01) and this was not seen in the AAO > 50 years group. The frequency of GBA mutations was higher in a subset of 178 cases that reported four Jewish grandparents (16.9%) than in cases who did not report Jewish ancestry (8.0%) (p < 0.01). Nine different GBA mutations were identified in PD cases, including 84insGG, E326K, T369M, N370S, D409H, R496H, L444P, RecNciI, and a novel mutation, P175P.
This study suggests that the Glucocerebrosidase gene may be a susceptibility gene for Parkinson disease and that Glucocerebrosidase mutations may modify age at onset.
评估参与帕金森病遗传流行病学（GEPD）研究的病例和对照中葡萄糖脑苷脂酶（GBA）突变的频率。
我们对GEPD研究中纳入的278例帕金森病（PD）患者和179名对照的GBA基因所有外显子进行了测序，这些患者和对照发病年龄（AAO）范围广泛，其中包括178例犹太裔患者和85名犹太裔对照的子集。病例和对照在招募时均不知晓帕金森病家族史，且在发病年龄＜50岁的类别中对病例进行了过度抽样。
13.7%的PD患者（38/278）携带GBA突变，而对照中这一比例为4.5%（8/179）（优势比[OR]3.4，95%置信区间1.5至7.4）。在90例发病年龄≤50岁的患者中GBA突变频率为22.2%，而在185例发病年龄＞50岁的患者中这一频率为9.7%（OR 2.7,95%置信区间1.3至5.3）。在对评估时的年龄、性别、帕金森病家族史和犹太血统进行校正后，GBA携带者帕金森病的发病年龄比非携带者早1.7年（95%置信区间0.5至3.3，p＜0.04）发病年龄≤50岁的携带者帕金森病平均发病年龄比非携带者早2.5年（95%置信区间0.6至4.5，p＜0.01）而在发病年龄＞50岁的组中未观察到这种情况。在报告有四位犹太祖父母的178例患者子集中GBA突变频率（16.9%）高于未报告有犹太血统的患者（8.0%）（p＜0.01）。在PD患者中鉴定出9种不同GBA突变，包括84insGG、E326K、T369M、N370S、D409H、R496H、L444P、RecNciI以及一种新突变P175P。
本研究提示葡萄糖脑苷脂酶基因可能是帕金森病的一个易感基因，且葡萄糖脑苷脂酶突变可能会改变发病年龄。
