Biomarkers for Posttraumatic Stress in Women Following a Campus Mass Shooting

描述（由申请人提供）：本研究的具体目的是利用创新的转化研究方法，利用基因-环境相互作用的方法来研究恐惧生理学、分子遗传学和创伤后应激症状（PTSS）之间的关系。恐惧抑制被认为是创伤后应激障碍（PTSD）的一种中间神经生物学表型，通常被认为是一种恐惧障碍。创伤后应激障碍是基因-环境相互作用方法的理想候选者；然而，现有的分子遗传学研究受到基因-环境相关性的限制（承认创伤暴露部分由遗传因素决定）。在2008年2月14日北伊利诺伊大学发生大规模枪击事件时，这项研究利用了一组独特的女性进行纵向研究。这种创伤暴露的致命性质使基因与环境相关的问题最小化。该研究建立在大规模枪击事件前广泛的创伤和心理健康史的基础上，并预测恐惧生理学和垂体腺苷酸环化酶激活多肽（PACAP）将介导致命的、共同的创伤和创伤后应激障碍之间的关系。最近的研究（Ressler et al, 2011）报告了PACAP与女性PTSD症状之间的联系，而不是男性。例如，在女性中，PACAP38血液水平与对危险线索（CS+）和安全线索（CS-）的惊吓反射显著增加之间存在关联，而在女性中，ADCYAP1R1受体SNP rs2267735与创伤后应激障碍和恐惧条件反射存在显著关联，而在男性中则没有。利用这个暴露于大规模枪击事件的独特队列的一个子集（建议N = 150），假设当前的恐惧生理学（例如，实验室恐惧增强了对恐惧条件提示的惊吓，恐惧歧视和恐惧消失，以及黑暗增强的惊吓），结合遗传和外周血水平标记（例如，PACAP），将预测从枪击前到枪击后（大约27天）评估的PTSS风险差异。尤其是那些在大规模枪击事件前有更广泛创伤史的女性。SNP rs2267735在雌激素反应元件中的位置有望解释PTSD的性别差异。为了研究雌激素对PACAP-PAC1基因表达的影响，我们假设ADCYAP1R1甲基化水平将与外周血雌激素水平较高而不是较低的个体的PTSS密切相关。预计这些发现将有助于了解分子遗传学与PTSD风险之间的联系，特别是PTSD的性别差异，最终导致更好地定制PTSD的治疗方法。

DESCRIPTION (provided by applicant): The specific aim of the proposed study is to utilize innovative translational research methods to examine the association between fear physiology, molecular genetics and posttraumatic stress symptoms (PTSS) using a gene-environment interaction approach. Inhibition of fear has been conceptualized as an intermediate neurobiological phenotype of posttraumatic stress disorder (PTSD), commonly viewed as a disorder of fear. PTSD is an ideal Candidate for a gene-environment interaction approach; however, existing molecular genetics research is hampered by the limitation of gene-environment correlation (which recognizes the fact that trauma exposure is in part determined by heritable factors). The proposed study utilizes a unique cohort of females enrolled in a longitudinal study at the time of a mass shooting at Northern Illinois University on February 14, 2008. The fateful nature of this trauma exposure minimizes the problem of gene-environment correlation. The proposed study builds upon the extensive trauma and mental health history available prior to the mass shooting and predicts that fear physiology and the pituitary adenylate cyclase-activating polypeptide (PACAP) will mediate the relationship between a fateful, shared trauma and PTSS. Recent research (Ressler et al., 2011) has reported a link between PACAP and PTSD symptoms in females but not males. For example, females demonstrated an association between PACAP38 blood levels and significantly increased startle reflexes to both the danger cue (CS+) and the safety cue (CS-), while the ADCYAP1R1 receptor SNP rs2267735 demonstrated significant association with PTSD and fear conditioning in females, but not males. Utilizing a subset (proposed N = 150) of this unique cohort exposed to a mass shooting, it is hypothesized that current fear physiology (e.g., laboratory fear potentiated startl to a fear conditioned cue, fear discrimination and fear extinction, as well as dark enhanced startle), combined with genetic and peripheral blood level markers (e.g., PACAP), will predict differential risk for PTSS as assessed from pre- to post-shooting (approximately 27 days post-shooting at Time 2), particularly among females who reported a more extensive trauma history prior to the mass shooting. The location of SNP rs2267735 within an estrogen response element holds promise in terms of explanatory power for sex differences in PTSD. To examine the impact of estrogen on PACAP-PAC1 gene expression, it is hypothesized that ADCYAP1R1 methylation levels will be most strongly related to PTSS among individuals with higher, as opposed to lower, levels of peripheral blood levels of estrogen. It is anticipated that findings wil inform understanding of the link between molecular genetics and the risk for PTSD, particularly with regard to sex differences in PTSD, ultimately leading to better tailoring of treatment methods for PTSD. PUBLIC HEALTH RELEVANCE: The proposed research aims to advance understanding of the underlying causes of posttraumatic stress disorder (PTSD), which is a recognized public health problem with significant societal and individual costs. The proposed research will explain the role that exaggerated physiological reactivity to startling stimuli, in combination with peripheral blood level markers of pituitary adenylate cyclase- activating polypeptide and estrogen, genetic factors, and past trauma history, plays in predicting posttraumatic stress following a campus shooting. This research will broaden understanding of the causes of PTSD and will shed light in particular on the nature of women's greater risk for PTSD.