Genetics, Endocrinology and PTSD Risk in the Population

描述(由申请人提供)：这项建议寻求在960人中检查导致创伤后应激障碍发展的基因-环境相互作用，这些人是从纽约大都会地区暴露于世界贸易中心袭击的2750名男性和女性中挑选出来的。这个队列最初是在9.11事件后六个月招募的，为了确定这一事件造成的精神健康后果，已经进行了纵向跟踪，并且足够大，足以对这种疾病的风险因素进行全面调查。我们将检查临床和神经内分泌指标，以前假设或证明与创伤后应激障碍风险相关，与皮质醇信号的改变有关。由于遗传因素参与了这一生物系统的功能，我们将研究与糖皮质激素活性相关的几个基因的多态性，以及与创伤后应激障碍病理生理学有关的肽能和单胺能神经传递。为了确定其他相关基因的参与，我们将使用微阵列技术和定量聚合酶链式反应来检测表达谱。被验证的基因子集也将进行与创伤后应激障碍相关的基因分型。此外，基于最近的非遗传性创伤后应激障碍和与创伤后应激障碍相关的皮质醇改变的代际传播的证据(即，创伤暴露的患有创伤后应激障碍的父母传递给他们的后代)，我们将通过表观遗传机制(例如，DNA甲基化)来检验稳定的个体基因活性差异，这些差异受到经验的影响。这些研究将集中在淋巴细胞中糖皮质激素受体(GR)的特定启动子区域，这一组织被证明在创伤后应激障碍中对糖皮质激素更敏感。因此，有可能将GR启动子区DNA甲基化的表观遗传学改变与“遗传和非遗传风险因素及其与创伤严重程度的相互作用”联系起来，以期了解创伤在创伤后的发展中的作用这一简单但尚未得到回答的问题，以及为什么有些人在创伤暴露后患上创伤后应激障碍，而另一些人则不会。这一独特和具有代表性的队列的巧合，加上这个多机构团队所反映的专业知识，将提供关于创伤后应激障碍的分子遗传学基础、创伤后应激障碍脆弱性和应激抵抗的明确信息。与公共卫生的相关性：对于为什么只有一些暴露在创伤中的人会患上创伤后应激障碍，而大多数人没有，这方面的知识存在很大差距。这种差距是由于过度强调创伤后应激障碍作为对事件的反应，而不是对使一些人更容易受到伤害的遗传或早期环境影响的差异的重视。只有在了解了个体风险因素及其与事件暴露的相互作用之后，才能制定预防和治疗创伤后应激障碍的模式。

DESCRIPTION (provided by applicant): This proposal seeks to examine gene-environment interactions that contribute to the development of PTSD in 960 persons selected from a well-characterized sample of 2750 men and women in the New York metropolitan area, exposed to the World Trade Center attacks. This cohort was initially recruited six months after September 11th, has been followed longitudinally for the purpose of determining mental health consequences resulting from this event, and is sufficiently large enough to undertake a comprehensive investigation of risk factors for this disorder. We will examine clinical and neuroendocrine measures previously hypothesized or demonstrated to be associated with risk for PTSD, related to alterations in cortisol signaling. Since genetic factors contribute to the function of this biological system, we will examine polymorphisms of several genes related to glucocorticoid activity, as well as peptidergic and monoaminergic neurotransmission implicated in PTSD pathophysiology. To determine the involvement of other relevant genes, we will examine expression profiles using microarray techniques and quantitative polymerase chain reaction. The subset of genes that are validated will also be genotyped for association with PTSD. Additionally, based on recent evidence for non-genetic intergenerational transmission of PTSD and cortisol alterations associated with PTSD (i.e., from trauma-exposed parents with PTSD to their offspring), we will examine stable individual differences in gene activity that are subject to 'programming' by experience via epigenetic mechanisms (e.g., DNA methylation). These studies will focus on specific promoter regions of the glucocorticoid receptor (GR) in lymphocytes, a tissue demonstrated to be more responsive to glucocorticoids in PTSD. It will therefore be possible to associate epigenetic alterations in DNA methylation at GR promoter sites with" genetic and non-genetic risk factors, and their interaction with trauma severity, towards the aim of understanding the simple, but as yet unanswered question of the role of trauma in the development of PTSD, and the even more complex one of why some persons develop PTSD following trauma exposure while others do not. The coincidence of this unique and representative cohort, together with the expertise reflected in this multi-institutional team, will provide unambiguous information concerning the molecular- genetic basis of PTSD, PTSD vulnerability, and stress resistance. Relevance to Public Health: There is a major gap in knowledge regarding why only some exposed to trauma develop PTSD, while the majority do not. This gap results from an over-emphasis on PTSD as a response to an event and an under-emphasis on differences in genetic or early environmental influences that make some more vulnerable. The development of models of prevention and treatment of PTSD can only occur following an understanding of individual risk factors and their interactions with event exposure.