Case-Control Studies Nested in National ALS Registry to Evaluate Environmental Risks

国家 ALS 登记处的病例对照研究用于评估环境风险

• 批准号: 9045228
• 负责人: HIROSHI MITSUMOTO
• 金额: $ 39.88万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2018-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9045228
• 关键词: Case; Control; Studies; Nested; National

 DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is considered the most devastating neurodegenerative disease. Patients suffer progressive functional loss, including loss of speech, swallowing, mobility, and respiration that leads to death on average 2 to 4 years after diagnosis. Except for aggressive symptomatic care, there are no effective treatments. More than 50 clinical trials based on plausible hypotheses of disease mechanisms have failed except for riluzole. Identified inherited pathogenic mutations account for ~10% of all ALS cases; the cause of most sporadic cases is unknown. ALS is now considered to be potentially caused by a combination of both genetic and environmental risk factors. Our overall hypothesis is that individual environmental risk factors reported to be associated with ALS act via a common mechanism, specifically oxidative stress (OS). Our NIEHS-funded prospective multicenter cohort study of ALS (ALS COSMOS), which investigates the extent to which multiple risk factors associated with OS are also associated with ALS progression, is in its final stages. Our current ARREST ALS project expands ALS COSMOS at a national level through the National ALS Registry, using structured telephone interviews and one-time urine and saliva collection. Now, we propose a set of well-designed, high-quality, case-control studies nested within ARREST ALS. We specifically aim: 1. To evaluate environmental and other risk factors in a population-based case-control study nested within the ARREST ALS study of the National ALS Registry. The cases (150 patients) will be identified in the on- going ARREST ALS project. We will match 2 controls to each case based on sex, age (± 5 years), race/ethnicity, and geographic area of residence. We will administer our well-validated, structured interview to determine cognitive function and obtain data on early life events and environmental, residential, occupational, dietary, lifestyle, and psychological factors. Dietary questionnaire data, first-void urine samples to measure OS markers, and saliva DNA will be collected; 2. To evaluate early life and late life environmental and other risk factors in a sibling-based, case-control study. We will identify a same-sex sibling who agrees to participate and is closest in age to the case. We estimate that 80% of cases will have a sibling who meets these criteria. They will receive the same risk factor assessment and provide saliva and urine samples as the population controls. 3. To evaluate individual or aggregate environmental risk factors between cases and controls at different stages of life and to investigate the significance of the urinary OS biomarker in relation to ALS and environmental risk factors. We will analyze risk factors at different stages of life in the two control groups combined in comparison to the cases and further analyze OS biomarkers in relation to risk factors. In summary, carefully designed population-based and sibling-based case-control studies nested within ARREST ALS will reveal entirely new and unique data concerning environmental risk factors, disease progression, and the potential cause(s) of ALS.

 描述（由申请人提供）：肌萎缩侧索硬化症（ALS）被认为是最具破坏性的神经退行性疾病。患者会出现进行性功能丧失，包括言语、吞咽、活动和呼吸丧失，平均在诊断后 2 至 4 年内导致死亡。除了积极的对症治疗外，没有有效的治疗方法。除利鲁唑外，基于疾病机制合理假设的 50 多项临床试验均已失败。已确定的遗传性致病突变约占所有 ALS 病例的 10%；大多数散发病例的原因尚不清楚。目前认为 ALS 可能是由遗传和环境风险因素共同引起的。我们的总体假设是，据报道与 ALS 相关的个体环境风险因素通过共同机制发挥作用，特别是氧化应激 (OS)。我们由 NIEHS 资助的 ALS 前瞻性多中心队列研究 (ALS COSMOS) 已进入最后阶段，该研究调查了与 OS 相关的多种危险因素在多大程度上也与 ALS 进展相关。我们当前的 ARREST ALS 项目通过国家 ALS 登记处，使用结构化电话访谈和一次性尿液和唾液收集，在国家一级扩展了 ALS COSMOS。现在，我们在 ARREST ALS 中提出了一套精心设计、高质量的病例对照研究。我们的具体目标是： 1. 在国家 ALS 登记处的 ARREST ALS 研究中进行的基于人群的病例对照研究中评估环境和其他风险因素。这些病例（150 名患者）将在正在进行的 ARREST ALS 项目中确定。我们将根据性别、年龄（± 5 岁）、种族/民族和居住地理区域为每个病例匹配 2 个对照。我们将进行经过充分验证的结构化访谈，以确定认知功能并获取有关早期生活事件以及环境、居住、职业、饮食、生活方式和心理因素的数据。将收集饮食问卷数据、用于测量 OS 标记的首次排尿样本以及唾液 DNA； 2. 在基于兄弟姐妹的病例对照研究中评估早年和晚年的环境和其他危险因素。我们将确定一名同意参与且年龄与病例最接近的同性兄弟姐妹。我们估计 80% 的病例都有符合这些标准的兄弟姐妹。他们将接受与对照组相同的风险因素评估，并提供唾液和尿液样本。 3. 评估不同生命阶段病例和对照之间的个体或总体环境危险因素，并研究尿液 OS 生物标志物与 ALS 和环境危险因素相关的意义。我们将结合病例分析两个对照组在不同生命阶段的危险因素，并进一步分析与危险因素相关的 OS 生物标志物。总之，ARREST ALS 中精心设计的基于人群和兄弟姐妹的病例对照研究将揭示有关环境风险因素、疾病进展和 ALS 潜在原因的全新且独特的数据。