Adverse Childhood Experience, Genes, and PTSD Risk in Soldiers: A Methylation Study
Adverse Childhood Experience, Genes, and PTSD Risk in Soldiers: A Methylation Study
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DOI：
10.1093/milmed/usz292
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发表时间：
2020-03-01
影响因子：
1.2
通讯作者：
Willis, Adam M.
中科院分区：
文献类型：
--
作者：
Hossack, Michael R.;Reid, Matthew W.;Willis, Adam M.
表观遗传学可以作为许多已知精神疾病易感性的标志。多个基因的DNA甲基化模式已在平民和军人创伤后应激障碍（PTSD）进行了研究。这些基因中的许多发挥各种功能，跨越下丘脑-垂体-肾上腺轴、免疫系统和中枢神经系统（CNS）生长因子和神经传递。人们认为，这些基因的甲基化水平可能能够识别出患PTSD风险较高的个体。我们的研究旨在建立是否以前报道的PTSD基因具有特定的甲基化模式，这是预测PTSD在现役军人与战斗exposure.Materials and MethodsThis是一个机构审查委员会（IRB）批准的，横截面，病例对照，基因环境相互作用的研究。招募了大约170名有或没有创伤后应激障碍的现役军人。排除了有结构性脑损伤、导致意识丧失的创伤性脑损伤（TBI）、PTSD或焦虑症的部署前诊断以及抗抑郁药或精神活性药物的部署前处方的患者。通过对所有受试者进行有效问卷调查，对儿童期创伤和逆境（不良童年经历[ACE]评分）、PTSD症状（PTSD检查表军事版[PCL-M]）和战斗暴露量表（CES）进行有效测量。从170名受试者提供的外周血中提取DNA后，我们通过焦磷酸测序测定以下7个基因中9个靶区域的甲基化百分比：BDNF，NR 3C 1，MAN 2C 1，TLR 8，SLC 6A 4，IL-18和SKA 2。这些基因在文献中通常被报道为与PTSD和早期生活创伤经历高度相关。甲基化水平测量为在先前提到的基因内的特定位点处的百分比。采用SPSS v22.0 Statistics和JMP v13.1软件对数据进行分析，使用一般线性模型对甲基化与创伤（CES评分）进行划分，根据PTSD的诊断与否、甲基化与儿童期创伤（ACE评分）以及甲基化与PTSD严重程度（PCL-M评分）进行划分。进行双因素方差分析，以抗抑郁药使用为对照。一个双尾学生t-检验进行PTSD分析，并与PTSD诊断，人口统计学信息以及ACE评分，PCL-M评分，和CES scores.ResultsDifferentially甲基化位点，高度相关的PTSD诊断中发现的7个候选基因：BDNF，NR 3C 1，和MAN 2C 1。与对照组相比，PTSD诊断患者的甲基化水平显着降低，即使在控制抗抑郁药使用后。PCL-M，ACE，和CES分数显着相关PTSDdiagnosis.ConclusionOur study suggests，甲基化的关键基因参与突触可塑性和下丘脑-垂体-肾上腺轴与低水平的甲基化暴露于战斗中的军事PTSD受试者相比，他们的非PTSD同行。这项研究的优势包括控制抗抑郁药的使用和排除TBI患者。在这种规模的现役人群中进行的类似研究很少。目前尚不清楚的是，甲基化变化是否是PTSD病理学的驱动因素，或者它们是否仅仅是疾病的标志。未来的研究领域包括前瞻性研究，测量同一个体战斗前和战斗后的甲基化暴露。
IntroductionEpigenetics can serve as a marker of susceptibility to many known psychiatric diseases. DNA methylation patterns of multiple genes have been studied in both civilian populations and military personnel with post-traumatic stress disorder (PTSD). Many of these genes serve various functions that span the hypothalamic-pituitary-adrenal axis, immune system, and central nervous system (CNS) growth factors and neurotransmission. It is thought that the methylation levels of such genes may be able to identify individuals who are at higher risk of developing PTSD. Our study seeks to establish whether previously reported PTSD genes possess a particular methylation pattern that is predictive of PTSD in active duty military members with combat exposure.Materials and MethodsThis is an institutional review board (IRB)-approved, cross-sectional, case control, gene-environment interaction study. About 170 active military members with and without PTSD were recruited. Patients with a history of structural brain damage, traumatic brain injury (TBI) resulting in loss of consciousness, predeployment diagnosis of PTSD or anxiety disorder, and predeployment prescription of an antidepressant or psychoactive medication were excluded. Validated measures of childhood trauma and adversity (adverse childhood experience [ACE] score), PTSD symptoms (PTSD check-list military version [PCL-M]), and combat exposure scales (CES) were measured via validated questionnaires for all subjects. After extracting DNA from peripheral blood provided by the 170 subjects, we determined methylation percentages, via pyrosequencing assays, for nine target areas within the following seven genes: BDNF, NR3C1, MAN2C1, TLR8, SLC6A4, IL-18, and SKA2. These genes are commonly reported in the literature as being highly correlated with PTSD and early-life traumatic experiences. Methylation levels were measured as a percentage at specific sites within the previously mentioned genes. Data were examined with SPSS v 22.0 Statistics and JMP v13.1 software using a general linear model for methylationxtrauma (CES scores) split by diagnosis of PTSD or not, methylation versus childhood trauma (ACE scores), and methylation versus PTSD severity (PCL-M score). Two-wayANOVAwas performed to control for antidepressant use. A two-tailed Student t-test was performed for PTSD analyses and was correlated with PTSD diagnosis, demographic information as well as ACE score, PCL-M score, and CES scores.ResultsDifferentially methylated sites that were highly associated with PTSD diagnosis were found in three of seven candidate genes: BDNF, NR3C1, and MAN2C1. When compared to controls, patients with PTSD diagnosis had significantly lower levels of methylation, even after controlling for antidepressant use. PCL-M, ACE, and CES scores were significantly associated with PTSD diagnosis.ConclusionOur study suggests that methylation of key genes involved in synaptic plasticity and the hypothalamic-pituitary-adrenal axis is associated with lower levels of methylation in military PTSD subjects exposed to combat when compared to their non-PTSD counterparts. Strengths of this study include controlling for antidepressant use and excluding TBI patients. Similar studies in an active duty population of this size are scarce. What is not clear is whether methylation changes are driving PTSD symptomology or whether they are merely a marker of disease. Future areas of research include prospective studies that measure methylation pre- and postcombat exposure in the same individual.