Identification and Characterization of Potential Environmental Risk Factors for ALS Using the ATSDR ALS Registry Cases and a Control Population

肌萎缩侧索硬化症(ALS)是成人最常见的运动神经元病，具有全球性 每年发病率为1-2.6/10万。已知的危险因素包括年龄、某些基因突变和男性。 在上了年纪之前。在病因不明的情况下，确定ALS的可改变的危险因素是一个重要的 减少这种疾病负担的方法；然而，对环境问题的研究结果并不一致 肌萎缩侧索硬化症的危险因素，如金属、溶剂和农药暴露，过去的研究仅限于其 有能力用个体水平的ALS风险因素和基因突变来检查是否存在基因突变 环境相互作用。尽管已经对环境空气污染物进行了其他神经学方面的检查 如帕金森氏症和阿尔茨海默氏症，到目前为止只有一项研究探索了 与肌萎缩侧索硬化症的潜在关系。这项研究旨在调查环境和职业之间的关系 暴露包括持久性环境毒物、环境空气污染物和肌萎缩侧索硬化症。病例对照 建议进行一项研究，并将涉及从国家ALS注册中心识别ALS患者 现有的生物储存库样本和风险因素数据(病例，n=330)，并从这些样本中招募对照人员 按年龄、种族和性别匹配的县或州(n=330)。调查问卷将获得有关以下方面的信息 社会人口因素、吸烟史、兵役史、环境/职业暴露 (农药、金属、溶剂)，以及终身居住和职业史。 将审查环境/职业暴露(即自我报告和环境空气污染物)与 通过验证血液样本中的毒物水平来评估ALS风险。住宅历史将被用来计算 2002-2012年期间PM2.5和臭氧的时间加权平均暴露量。关于35种神经毒性空气的数据 通过美国环保局全国范围空气毒性评估(NATA)确定的污染物将被用于 计算病例和对照的病例和对照的年均平均住宅暴露量(1999年， 2002年、2005年和2011年)。我们将测量血液中溶剂和杀虫剂的暴露浓度 使用一组持久性环境污染物测试的病例(n=330)和对照(n=330) (有机氯农药、多氯联苯和溴化阻燃剂)。这将有助于验证 对估计暴露的反应。优势比和95%的CI将使用条件Logistic进行估计 对人口统计、混杂因素和吸烟进行调整后的回归。此外，在ALS病例中 (n=330)，我们将研究环境毒物在人类生物学中的功能关系。 与此相关的样本和关键生物学途径和共同基因(如C9ORF72、SOD1、NEK1) 肌萎缩侧索硬化症的发展和/或进展。这项拟议的研究将是第一批检测血液中 环境毒物和基因突变的存在，并结合环境和 访谈数据中的职业暴露(即自我报告和环境空气污染物)与肌萎缩侧索硬化症风险的关系。

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults and has a global incidence of 1-2.6/100,000 annually. Known risk factors include age, certain genetic mutations, and male sex prior to older age. With largely unknown etiology, identifying modifiable risk factors for ALS is an important approach to minimizing the burden of this disease; however, findings have been inconsistent for environmental risk factors for ALS, such as metal, solvent, and pesticide exposure and past studies have been limited in their ability to examine the presence of genetic mutations with individual level risk factors for ALS and gene- environment interactions. Although ambient air pollutants have been examined with regard to other neurologic conditions, such as Parkinson’s disease and Alzheimer’s disease, only one study to date has explored the potential relationship with ALS. The study aims to investigate associations of environmental and occupational exposures including persistent environmental toxicants and ambient air pollutants and ALS. A case control study is proposed and will involve identification of persons with ALS from the National ALS Registry with available biorepository samples and risk factor data (cases, n=330), and recruitment of controls from the same county or state matched by age, race, and sex (n=330). The questionnaire will obtain information on sociodemographic factors, smoking history, military service history, environmental/occupational exposures (pesticides, metals, solvents), and lifetime residential and occupational history, as available. Environmental/occupational exposures (i.e., self-report and ambient air pollutants) will be examined in relation to ALS risk with verification of toxicant levels in blood samples. Residential history will be used to calculate a time weighted average exposure of PM2.5 and ozone for the period 2002-2012. Data on 35 neurotoxic air pollutants identified through the US EPA National-Scale Air Toxics Assessment (NATA) will be used to calculate average annual average residential exposure for cases and controls for available NATA years (1999, 2002, 2005, and 2011). We will measure exposures to solvents and pesticides in blood concentrations of cases (n=330) and controls (n=330) using a battery of tests for persistent environmental pollutants (organochlorine pesticides, polychlorinated biphenyls, and brominated flame retardants). This will help verify the responses for estimated exposures. Odds ratios and 95% CIs will be estimated using conditional logistic regression with adjustment for demographics, confounders, and smoking. Additionally, among ALS cases (n=330), we will examine the functional relationship between environmental toxicants in human biological samples and key biological pathways and common genes (e.g., C9ORF72, SOD1, NEK1) associated with the development and/or progression of ALS. The proposed study will be one of the first to examine blood levels of environmental toxicants and presence of genetic mutations in combination with data on environmental and occupational exposures from interview data (i.e., self-report and ambient air pollutants) in relation to ALS risk.