Lead And Other Neurotoxins As Risk Factors For Amyotrophic Lateral Sclerosis

我们在新英格兰进行了一项ALS病例对照研究。 具体目的是描述ALS与以下因素的潜在关联：（i）铅暴露;（ii）其他神经毒素暴露，如汞、溶剂和农药;（iii）生活方式因素，如吸烟和饮食;（iv）影响神经功能或铅代谢的遗传多态性。 在马萨诸塞州波士顿的两家医院招募病例（N=109）。 通过随机数字拨号确定的人群对照（N=256）与新英格兰内年龄、性别和居住地区的病例频率匹配。 我们收集的信息，职业，住宅和娱乐接触铅使用结构化访谈。 此外，我们还测量了血液和骨铅水平，后者使用体内K X射线荧光（K-XRF），并存档全血和血清样本用于基因-环境相互作用的研究。 我们已经探讨了ALS与几种生活方式因素的关系。 吸烟与ALS风险增加1.7倍相关，但饮酒与ALS无关。 ALS家族史也与风险增加有关。 我们检查了钙、镁和抗氧化剂的饮食摄入量。 总的来说，这些饮食因素与ALS风险无关，尽管镁和番茄红素有适度的保护作用。 对ALS与铅暴露关系的分析发现，ALS的风险与自我报告的铅职业暴露增加1.9倍有关，并与铅暴露的剂量反应有关。 ALS风险也与血铅和骨铅水平升高相关：血铅每增加mg/dl，ALS风险增加1.9倍，对数转换髌骨电极导线每增加1单位，ALS风险增加3.6倍，对数转换胫骨电极导线每增加1单位，ALS风险增加2.3倍。 这些结果扩展了以前的报告完全基于访谈数据，首次显示了ALS与铅生物标志物的关联，并表明铅暴露在ALS病因学中的潜在作用。 我们已经探索了遗传易感性在ALS中的作用。 具体来说，我们评估了ALS与δ-氨基乙酰丙酸脱氢酶（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等位基因与髌骨和胫骨中铅水平降低相关，但与血液中的铅水平无关，并且与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多态性所赋予的遗传易感性可能会影响ALS的风险，可能是通过与内部铅暴露相关的机制。 我们还研究了ALS与血管内皮生长因子（VEGF）的关系，VEGF是一种介导缺氧反应的血管生成生长因子。 我们证实了以前的报道，即ALS的风险与VEGF启动子区的多态性有关，这决定了两种特定的单倍型。 这些结果表明，ALS的发病机制可能涉及对缺氧的反应受损。 最近的一项分析发现，头部创伤与ALS有关，特别是多发性和近期创伤;这项研究目前正在出版中。 另外几项分析正在进行中。 使用从国家死亡指数中检索到的死亡日期和原因信息，我们发现ALS病例的进展率与铅暴露有关;这项研究已提交出版。 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处显示ALS的风险与儿童期暴露相关，包括母亲年龄和年幼兄弟姐妹的数量;这项研究已提交出版。 我们正在研究ALS与DNA修复酶和血清蛋白质谱多态性的关系。 我们还开始了一项新的数据收集工作，即与杜克大学和达勒姆退伍军人管理医院的研究人员合作进行的ALS和铅暴露退伍军人（VALE）研究。 VALE研究为正在进行的病例对照研究增加了一个组成部分，以收集100例ALS病例和200例匹配对照的重金属暴露测量样本，以证实我们最初发现的铅暴露与ALS的关联。

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.