Pre-disease biomarkers of persistent organic pollutants, immune system, and amyotrophic lateral sclerosis

项目总结/摘要 我们建议研究持久性有机污染物（POP）的血液浓度之间的关系， 和肌萎缩侧索硬化症（ALS）的发病率和生存率，使用的血液样本收集之前， ALS的发病。我们还将探讨这些暴露和ALS是否与以下变化相关： 细胞外囊泡（EV）特异性来源于免疫系统细胞，以确定与免疫系统相关的机制。 他们之间的关系，以及他们之间的关系。我们将进行一项病例对照研究， 在丹麦和芬兰进行的前瞻性队列研究，共有近12万名参与者。与会者 提供了队列基线的血液样本，我们通过与以下因素的联系在随访期间识别ALS病例： 国家登记册。我们预计队列入组后共发生265例ALS病例。我们将 从所有非ALS患者中随机选择2名年龄、性别和队列匹配的对照组 在确诊病例时仍存活的病例。来自队列的广泛问卷数据可用于 回归模型调整。血液样本将进行有机氯农药分析， 多氯联苯（PCB）和多溴二苯醚（PBDEs）。电动汽车将被隔离， 以大小和数量以及表达特异性表面标志物的百分比来表征，所述特异性表面标志物 来自免疫系统细胞的EV。通过将这项研究嵌套在大型丹麦语和芬兰语 前瞻性队列研究有ALS前多年的血液样本，我们有一个独特的环境， 这将使我们第一次评估有毒物质暴露与ALS之间的关系， 从ALS发作前收集的样品中暴露的生物标志物，从而避免与ALS相关的问题。 在ALS发作后收集的样本中， 可能受到疾病的影响（导致可能的反向因果关系）。患病前的生物样本也让我们 探索可能构成我们所看到的关联的生物学机制，并可能确定生物标志物， 未来疾病风险和生存的预测，从而提供对ALS病理生理学的深入了解。

Project Summary/Abstract We propose to study the relation between blood concentrations of persistent organic pollutants (POPs) and amyotrophic lateral sclerosis (ALS) incidence and survival using blood samples collected well before the onset of ALS. We will also explore whether those exposures, and ALS, are associated with changes in extracellular vesicles (EV) derived specifically from immune system cells to identify mechanisms related to the exposures, ALS, and associations between them. We will conduct a case-control study nested within large prospective cohort studies in Denmark and Finland that total almost 120,000 participants. The participants provided blood samples at the cohort baselines, and we identify ALS cases during follow-up via linkage with National registries. We anticipate a total of 265 ALS cases that occurred after cohort enrollment. We will randomly select 2 controls per case individually matched on age, sex, and cohort from among all non-ALS cases alive at the time the case is diagnosed. Extensive questionnaire data from the cohorts is available for regression model adjustments. The blood samples will be analyzed for organochlorine pesticides, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs). EVs will be isolated and characterized in terms of size and number, and percentage expressing specific surface markers that identify EVs derived from cells of the immune system. By nesting this study within large Danish and Finnish prospective cohort studies that have blood samples from many years before ALS, we have a unique setting that will allow us for the first time to assess the relation between toxicant exposures and ALS using individual biomarkers of exposure from samples collected before ALS onset, thereby avoiding problems associated with questionnaire recall of past exposures or biomarker measurements in samples collected after ALS onset that may be affected by disease (leading to possible reverse causation). The pre-disease biosamples also allow us to explore biological mechanisms that may underlie the associations we see and possibly identify biomarkers of future disease risk and survival, thereby providing insight into ALS pathophysiology.