Lead And Other Neurotoxins As Risk Factors For Amyotrophic Lateral Sclerosis

我们在新英格兰进行了一项ALS的病例对照研究。具体目的是确定ALS与(I)铅暴露的潜在联系；(Ii)暴露于其他神经毒素，如汞、溶剂和杀虫剂；(Iii)吸烟和饮食等生活方式因素；以及(Iv)影响神经功能或铅代谢的基因多态。病例(N=109)在马萨诸塞州波士顿的两家医院招募。通过随机数字拨号确定的人群对照(N=256)与新英格兰地区内年龄、性别和居住地区的病例频率相匹配。我们通过结构化访谈收集了有关铅的职业、居住和娱乐暴露的信息。此外，我们测量了血液和骨铅水平，后者使用活体K-X-射线荧光(K-XRF)，并存档了全血和血清样本，用于研究基因与环境的相互作用。 我们探讨了肌萎缩侧索硬化症与多种生活方式因素的关系。吸烟与肌萎缩侧索硬化症风险增加1.7倍相关，但饮酒与肌萎缩侧索硬化症无关。肌萎缩侧索硬化症家族史也与风险增加相关。我们检查了饮食中钙、镁和抗氧化剂的摄入量。总体而言，这些饮食因素与肌萎缩侧索硬化症的风险无关，尽管建议对镁和番茄红素有适度的保护作用。 对肌萎缩侧索硬化症与铅暴露关系的分析发现，肌萎缩侧索硬化症的风险与自我报告的职业铅暴露增加1.9倍有关，并具有终生铅暴露天数的剂量反应。ALS的风险也与血铅和骨铅水平的升高有关：血铅每增加1.9 mg/dl，经对数转化的膝盖骨铅每单位增加3.6倍，经对数转化的胫骨铅每单位增加2.3倍。这些结果扩展了之前完全基于访谈数据的报道，首次显示了ALS与铅生物标志物的关联，并暗示了铅暴露在ALS病因中的潜在作用。 我们已经探索了遗传易感性在ALS中的作用。具体地说，我们评估了ALS与β-氨基酮丙酸脱水酶(ALAD)和维生素D受体(VDR)基因多态性的关系，这两个基因都与铅易感性有关。ALAD 2等位基因与膝盖骨和胫骨的铅水平降低有关，但与血液中的铅水平无关，并与ALS风险增加1.9倍相关。相反，VDR B等位基因与铅水平或ALS风险无关。这些新的发现表明，ALAD基因多态带来的遗传易感性可能会影响ALS风险，可能是通过与体内铅暴露有关的机制。我们还研究了ALS与血管内皮生长因子(VEGF)的关系，血管内皮生长因子是一种介导对低氧反应的血管生成生长因子。我们证实了先前的报道，即ALS的风险与决定两种特定单倍型的VEGF启动子区域的多态有关。这些发现提示ALS的发病机制可能与低氧反应受损有关。 最近的一项分析发现，头部创伤与肌萎缩侧索硬化症有关，特别是多发性和近期创伤；这项研究目前正在进行中。其他几项分析正在进行中。使用从国家死亡指数中检索的死亡日期和死因信息，我们发现在ALS病例中，进展速度与铅暴露有关；这项研究已提交发表。在与瑞典卡罗林斯卡研究所的研究人员合作中，我们使用瑞典国家登记表明，ALS的风险与儿童时期的暴露有关，包括母亲的年龄和年幼兄弟姐妹的数量；这项研究已提交发表。我们正在研究肌萎缩侧索硬化症与DNA修复酶和血清蛋白图谱的多态之间的关系。 我们还与杜克大学和达勒姆退伍军人管理医院的研究人员合作，开始了一项新的数据收集工作，即退伍军人ALS和铅暴露(VALE)研究。淡水河谷的研究在正在进行的病例对照研究中增加了一个组成部分，目的是收集样本，用于测量100例ALS病例和200名匹配的对照组的重金属暴露，以证实我们最初发现铅暴露与ALS有关。

We conducted a case-control study of ALS in New England. Specific aims were to characterize potential associations of ALS with (i) lead exposure; (ii) exposure to other neurotoxins, eg, mercury, solvents and pesticides; (iii) lifestyle factors such as cigarette smoking and diet; and (iv) genetic polymorphisms affecting neurologic function or lead metabolism. Cases (N=109) were recruited at two hospitals in Boston, MA. Population controls (N=256) identified by random digit dialing were frequency matched to cases by age, sex, and region of residence within New England. We collected information on occupational, residential, and recreational exposure to lead using a structured interview. In addition, we measured blood and bone lead levels, the latter using in vivo K x-ray fluorescence (K-XRF), and archived whole blood and serum samples for studies of gene-environment interaction. We have explored the relationship of ALS to several lifestyle factors. Cigarette smoking was associated with 1.7-fold increase in ALS risk, but alcohol use had no relationship to ALS. Family history of ALS was also associated with increased risk. We examined dietary intake of calcium, magnesium, and antioxidants. Overall, these dietary factors were not related to ALS risk, although modestly protective associations were suggested for magnesium and lycopene. Analyses of the relationship of ALS to lead exposure found that risk of ALS was associated with a 1.9-fold increase in self-reported occupational exposure to lead, with a dose-response for lifetime days of lead exposure. Risk of ALS was also associated with elevations in both blood and bone lead levels: it was increased 1.9-fold for each mg/dl increase in blood lead, 3.6-fold for each unit increase in log-transformed patella lead, and 2.3-fold for each unit increase in log-transformed tibia lead. These results extend previous reports based entirely on interview data, showing for the first time an association of ALS with lead biomarkers, and suggest a potential role for lead exposure in the etiology of ALS. We have explored the role of genetic susceptibility in ALS. Specifically, we evaluated the relationship of ALS to polymorphisms in the genes for delta-aminolevulinic acid dehydratase (ALAD) and the vitamin D receptor (VDR), which have both been implicated in lead susceptibility. The ALAD 2 allele was associated with decreased lead levels in both patella and tibia, although not in blood, and with 1.9-fold increase in ALS risk. In contrast, the VDR B allele was not associated with lead levels or ALS risk. These novel findings suggest that genetic susceptibility conferred by polymorphisms in ALAD may affect ALS risk, possibly through a mechanism related to internal lead exposure. We also investigated the relationship of ALS to vascular endothelial growth factor (VEGF), an angiogenic growth factor that mediates responses to hypoxia. We confirmed previous reports that risk of ALS is associated with polymorphisms in the VEGF promoter region that determine two specific haplotypes. These findings suggest that the mechanism of ALS pathogenesis may involve impaired response to hypoxia. A recent analysis found that head trauma was associated with ALS, particular multiple and recent trauma; this study is now in press. Several additional analyses are in progress. Using information on date and cause of death retrieved from the National Death Index, we found that among ALS cases the rate of progression was related to lead exposure; this study has been submitted for publication. In a collaboration with researchers from the Karolinska Institute in Sweden, we used Swedish national registries to show that risk of ALS was associated with childhood exposures including maternal age and number of younger siblings; this study has been submitted for publication. We are investigating the relationship of ALS to polymorphisms in DNA repair enzymes and serum protein profiles. We have also begun a new data collection effort, the Veterans with ALS and Lead Exposure (VALE) Study, in collaboration with researchers at Duke University and the Durham Veterans Administration Hospital. The VALE study adds a component to an ongoing case-control study in order to collect samples for measurement of heavy metal exposure in 100 ALS cases and 200 matched controls, in order to corroborate our original finding of an association of lead exposure with ALS.