Epigenetic Linkage Between PTSD and Respiratory Disease in WTC Responders

描述（由申请人提供）：2001年9月11日对世界贸易中心（WTC）的恐怖袭击是一场非同寻常的环境灾难，对救援和恢复工作人员的身体和情感暴露前所未有。直接结果是，参加世贸中心卫生方案（WTC-HP）的世贸中心救灾人员表现出持续的创伤后应激障碍（PTSD）症状和与其暴露严重程度相关的呼吸道疾病。事实上，四分之一受这些条件影响的响应者同时患有这两种疾病。心身共病导致残疾和医疗服务利用率增加。该提案侧重于潜在的机制PTSD/呼吸系统合并症，可能有助于开发更有效的，理论驱动的干预措施，这些难以治疗的患者。本提案的总体目标是阐明 通过表观遗传学方法将创伤后应激障碍和WTC应答者的下呼吸道症状（LRS）联系起来。鉴于从WTC暴露到PTSD到呼吸系统疾病的途径的观察数据的纵向发现和支持性生物学数据，生态基因组学是理解免疫失调的合理下一步，从而随着时间的推移增加症状的持续性。从长远来看，使用Uddin等人描述的方法鉴定生物标志物可能有助于发现新的工具来遗传表征反应者中PTSD和呼吸道疾病的不同途径。具体研究目的是：1.确定并比较WTC-PTSD患者、从未发生PTSD的患者和未受创伤的健康对照组外周血DNA的甲基化模式。我们还将确定在WTC群组中观察到的甲基化模式是否：与来自底特律地区社区研究（Uddin et al.2010）的发现相当，慢性WTC-PTSD患者和缓解期PTSD患者相似;以及2.检查长岛临床应答者中甲基化模式的差异，这些应答者患有（a）WTC-PTSD和呼吸系统疾病共病，（B）仅呼吸系统疾病，（c）仅WTC-PTSD，和（d）既无呼吸系统疾病也无WTC-PTSD。 为了实现这些目标，我们将使用HumanMethylation 450 BeadChip和Infinium检测试剂盒对这些患者的外周血进行全基因组甲基化检测，并比较甲基化模式，以确定区分目标1和2中概述的组的生物标志物。此外，我们将验证特定基因座中的甲基化差异。 公共卫生相关性：总之，近年来在生态基因组学领域取得了巨大进展。虽然特别关注WTC-HP中的PTSD/呼吸道共病，但最终，我们的新方法旨在更好地了解暴露于极端事件如何“深入皮肤”，共同塑造身心健康结果，并引起共病。这项拟议的研究将表观遗传学原理应用于一个基于人群的队列，这是迄今为止通过这些方法调查的最大的队列之一。

DESCRIPTION (provided by applicant): The September 11, 2001 terrorist attack on the World Trade Center (WTC) was an extraordinary environmental disaster containing an unprecedented combination of physical and emotional exposures to rescue and recovery workers. As a direct result, WTC disaster responders attending the WTC Health Programs (WTC-HP) exhibit persistent symptoms of post-traumatic stress disorder (PTSD) and respiratory illness linked to the severity of their exposures. Indeed, one-quarter of responders affected by these conditions suffer from both. Mental-physical comorbidity leads to increased disability and utilization of medical services. This proposal focuses on potential mechanisms underlying PTSD/respiratory comorbidity that may facilitate development of more effective, theory-driven interventions for these difficult to treat patients. The overall goal of this proposal is to explicate the mechanisms linking PTSD and lower respiratory symptoms (LRS) in WTC responders through an epigenetics approach. Given longitudinal findings from observational data on the pathway from WTC exposures to PTSD to respiratory illness and supportive biological data, ecogenomics is the logical next step for understanding immune dysregulation and thus increased persistence of symptoms over time. In the long-term, identification of biomarkers using the approach described in Uddin et al. may help to uncover new tools to genetically characterize different pathways to PTSD and respiratory illness in responders. The specific aims of study are: 1. to determine and compare the methylation pattern of the peripheral blood DNA of patients with WTC-PTSD, patients who never developed PTSD, and a non-traumatized healthy control group. We will also determine whether the methylation patterns observed in the WTC cohort are: comparable to findings from the Detroit-area community study (Uddin et al. 2010) similar for patients with chronic WTC-PTSD and those with PTSD in remission; and 2. To examine differences in methylation patterns among Long Island clinic responders with (a) comorbid WTC-PTSD and respiratory illness, (b) only respiratory illness, (c) only WTC-PTSD, and (d) neither respiratory illness nor WTC-PTSD. To accomplish these AIMS we will conduct whole-genome methylation assays on peripheral blood from these patients using the HumanMethylation450 BeadChip and Infinium assay and compare methylation patterns to identify biomarkers which differential the groups outlined in Aims 1 and 2. In addition, we will validate methylation differences in specific loci. PUBLIC HEALTH RELEVANCE: In sum, recent years have seen enormous progress in the field of ecogenomics. Although focused specifically on PTSD/respiratory comorbidity in the WTC-HP, ultimately, our novel approach aims to better understand how exposure to extreme events 'gets under the skin' and jointly shapes physical and mental health outcomes, and gives rise to comorbid conditions. The proposed study applies epigenetic principles to a population-based cohort, one of the largest to be investigated by these methods to date.