Establishing the Cohort for Occupational Risk and Prevention Studies for Amyotrophic Lateral Sclerosis (ALS CORPS)

摘要 肌萎缩侧索硬化症（ALS）是一种进行性、致命的运动神经元疾病，可能是由于 终身非遗传性疾病（定义为ALS疾病组）和潜在遗传风险的组合。 通过ALS病例对照研究，我们确定了生产职业工人和职业病工人 金属暴露具有更高的ALS风险;因此，我们有兴趣了解这些职业性的 暴露和麻烦与遗传学相互作用，为ALS预防工作提供信息。关于RFA-TS- 23-001资助方案A，我们将通过建立一个纵向的个人队列来满足这一需求， 较高的ALS风险，职业和职业性金属暴露，以促进ALS基因和 麻烦的研究。在这一前瞻性的高危人群纵向队列中，我们将监测ALS 真实的时间内的麻烦、多基因风险和表型转换。我们的总体目标是识别累积风险 导致ALS表型转化的因素。我们的中心假设是，ALS是一个麻烦， 潜在的遗传风险有助于疾病表型转化并为ALS预防提供了靶点。我们 以初步数据为指导，表明：i）生产职业和职业金属接触 与ALS风险密切相关，ii）职业暴露以外的因素也有助于ALS风险，以及iii） 多基因风险的遗传结构有助于ALS风险。我们的理由是，一个前瞻性的队列将 能够确定关键的暴露窗口或暴露相互作用，可以有针对性地预防 ALS表型转化的高危人群。我们将通过三个目标来检验中心假设。目标1： 将建立一个前瞻性的，纵向队列的5,000人具有较高的ALS风险的基础上建立的 通过有针对性的在线招聘来消除职业风险因素。在目标2中，我们将使用详细的曝光 用于确定职业、住宅、日常生活和生活方式暴露的评估工具（ALS量表） 累积起来会增加ALS的风险我们还将获得所有人表型转化的早期指标， 参与者，包括体重指数和轻度运动和认知障碍，以建立队列的 暴露风险和表型转化指数，从而允许未来对ALS的关键研究 风险与预防。最后，在目标3中，我们将通过基因分型确定队列中ALS的多基因风险 来自参与者的口腔DNA，以建立与ALS染色体组整合的基线遗传风险。的 拟议的研究是非常重要的，因为我们希望（1）建立一个第一类，非家族性，但在风险 具有详细的基线麻烦组表型和表型转化标志物评估的ALS队列， (2)评估多基因风险以进一步分层ALS风险。纵向随访将确定关键时间窗 当干预措施可以改变疾病发作时。这是一个高影响力的提案，将ALS研究扩展到 从单纯的“治疗”方法转变为“预防”方法的范例。

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a progressive, fatal motor neuron disease that likely results from a combination of lifetime non-genetic exposures—defined as the ALS exposome—and underlying genetic risk. Through ALS case-control studies, we identified that workers in Production Occupations and with occupational metal exposures carry a higher ALS risk; thus, we are interested in understanding how these occupational exposures and the exposome interact with genetics to inform ALS prevention efforts. In response to RFA-TS- 23-001 Funding Option A, we will address this need by establishing a longitudinal cohort of individuals at higher ALS risk, enriched by occupation and occupational metal exposure, to facilitate ALS gene and exposome studies. In this prospective longitudinal cohort of at-risk individuals, we will monitor the ALS exposome, polygenic risk, and phenoconversion in real time. Our overall objective is to identify cumulative risk factors that contribute to ALS phenoconversion. Our central hypothesis is that the ALS exposome and underlying genetic risk contribute to disease phenoconversion and provide targets for ALS prevention. We are guided by preliminary data showing that: i) work in Production Occupations and occupational metal exposure strongly associate with ALS risk, ii) factors beyond occupational exposures also contribute to ALS risk, and iii) genetic architecture by polygenic risk contributes to ALS risk. Our rationale is that a prospective cohort will enable ascertainment of critical exposure windows or exposure interactions, which can be targeted to prevent ALS phenoconversion in persons at higher risk. We will test the central hypothesis via three aims. In Aim 1, we will establish a prospective, longitudinal cohort of 5,000 individuals with higher ALS risk based on established occupational risk factors by recruiting via targeted online postings. In Aim 2, we will use our detailed exposure assessment tools to ascertain occupational, residential, avocational, and lifestyle exposures (ALS exposome) which cumulatively contribute to ALS risk. We will also obtain early indicators of phenoconversion for all participants, including body mass index and mild motor and cognitive impairment, to establish the cohort’s exposure risks and phenoconversion indices at baseline, thereby allowing for future critical research on ALS risk and prevention. Finally, in Aim 3, we will determine the polygenic risk of ALS in the cohort by genotyping buccal DNA from participants to establish the baseline genetic risk to integrate with the ALS exposome. The proposed research is highly significant because we expect to (1) establish a first in kind, non-familial but at-risk ALS cohort with detailed baseline exposome phenotyping and assessment of phenoconversion markers and (2) assess polygenic risk to further stratify ALS risk. Longitudinal follow-up will identify the critical time windows when interventions can modify disease onset. This is a high impact proposal, expanding ALS research beyond a “treatment” only approach, to a paradigm that addresses a “prevention” approach.