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

项目摘要/摘要 我们建议研究持久性有机污染物(POPs)的血液浓度之间的关系 以及肌萎缩侧索硬化症(ALS)的发病率和存活率 肌萎缩侧索硬化症发作。我们还将探索这些暴露和ALS是否与 特异性来源于免疫系统细胞的细胞外小泡(EV)，以确定与 暴露、肌萎缩侧索硬化症以及它们之间的联系。我们将进行一项嵌套的病例对照研究 丹麦和芬兰的前瞻性队列研究，总共有近12万名参与者。参赛者 提供了队列基线的血液样本，我们在随访期间通过与 国家登记处。我们预计在队列登记后发生的ALS病例总数为265例。我们会 从所有非肌萎缩侧索硬化症患者中随机选择两个年龄、性别和队列匹配的病例作为对照 确诊时仍活着的病例。来自队列的广泛调查问卷数据可用于 回归模型调整。血液样本将被分析有机氯农药， 多氯联苯(PCbs)和多溴联苯醚(PBDEs)。电动汽车将被隔离并 以大小和数量以及表达识别特定表面标记的百分比为特征的 肠道病毒来源于免疫系统的细胞。通过将这项研究嵌套在大型丹麦和芬兰 拥有ALS前多年血液样本的前瞻性队列研究，我们有一个独特的环境 这将使我们能够第一次使用个人评估毒物暴露和ALS之间的关系 在肌萎缩侧索硬化症发病前收集的样本中暴露的生物标志物，从而避免与 在ALS发病后收集的样本中过去暴露或生物标记物测量的问卷回忆 可能受到疾病的影响(导致可能的反向因果关系)。疾病前的生物样本也让我们 探索可能是我们所看到的关联的基础的生物学机制，并可能识别生物标志物 对未来疾病风险和存活率的预测，从而提供对ALS病理生理学的洞察。

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.