Traumatic Stress and Accelerated Aging in DNA Methylation

 描述(申请人提供)：最近对衰老遗传学的研究表明，生物衰老部分受表观遗传控制，脱氧核糖核酸 (DNA)甲基化情况可能是表观遗传时钟的一个指数，这对调节细胞衰老很重要(例如，Horvath，2013)。甲基化影响发育过程，对细胞分化和环境适应至关重要；它通过抑制或激活基因转录来调节基因的表达(Szyf，2013)。几位研究人员已经开发了使用甲基化图谱来索引细胞年龄的算法(Hannum等人，2013年；Horvath，2013；Weidner等人，2014年)。这一发现为研究可能改变生物衰老速度的因素铺平了道路。该项目将使用多变量数据分析来评估创伤暴露和创伤应激(由创伤后应激障碍(PTSD)症状严重程度定义)是否与细胞加速老化有关，使用DNA甲基化年龄作为细胞年龄的指标。分析还将测试DNA甲基化年龄是否调节创伤应激和代谢综合征之间的联系，代谢综合征是一种与年龄相关的身体健康问题，已被证明与创伤后应激障碍共同发生(Bartoli等人，2013年)。其他分析将进一步探索创伤应激和DNA甲基化年龄之间的假设联系，以评估这是否由特定的生物学途径和细胞衰老所涉及的遗传变异所驱动。这将使用从美国退伍军人事务部的两个样本中提取的现有数据来实现，由于他们共享的方法，这两个样本可以结合在一起，产生685个非西班牙裔白人参与者的总样本量。第一个样本包括在持久行动或伊拉克自由行动中服役的美国退伍军人，第二个样本包括创伤暴露的美国退伍军人及其创伤暴露的配偶的子集。这两个样本都完成了结构化的精神诊断访谈，并提供了用于提取DNA的血液样本。关于基因组范围和表观基因组范围变异的信息分别在Illumina Omni250万和Infinium Humanmetylation450珠芯片阵列上进行了评估。该项目可能有助于确定与甲基组中细胞衰老速度相关的不利环境因素的特征，并发现创伤应激相关疾病的新分子途径。这将有助于确定哪些人面临加速老龄化及其负面健康后果的最大风险。在改变风险因素以达到改善健康的最终目标之前，这是必要的第一步。

 DESCRIPTION (provided by applicant): Recent research focused on the genetics of aging suggests that biological aging is partially under epigenetic control and that deoxyribonucleic acid (DNA) methylation profiles may be an index of the epigenetic clock that is important for regulating cellular aging (e.g., Horvath, 2013). Methylation influences developmental processes and is critical for cell differentiation and adaptation to the environment; it regulates the expression of the gene by suppressing or activating gene transcription (Szyf, 2013). Several investigators have developed algorithms to use methylation profiling to index cellular age (Hannum et al., 2013; Horvath, 2013; Weidner et al., 2014). This discovery paves the way for research into the factors that may alter the rate of biological aging. This project will use multivariate data analyses to evaluate if trauma exposure and traumatic stress, as defined by posttraumatic stress disorder (PTSD) symptom severity, are associated with accelerated cellular aging using DNA methylation age as the index of cellular age. Analyses will also test if DNA methylation age mediates the association between traumatic stress and metabolic syndrome, an age-related physical health problem that has been shown to co-occur with PTSD (Bartoli et al., 2013). Additional analyses would further explore the hypothesized association between traumatic stress and DNA methylation age to evaluate if this is driven by specific biological pathways and genetic variants implicated in cellular aging. This will be accomplished using existing data drawn from two U.S. Department of Veterans Affairs samples that can be combined as a result of their shared methodologies, yielding a total sample size of 685 white, non-Hispanic participants. The first sample comprises U.S. military veterans who served in Operation Enduring or Iraqi Freedom and the second sample consists of trauma- exposed U.S. military veterans and a subset of their trauma-exposed spouses. Both samples completed structured psychiatric diagnostic interviews and provided blood samples for DNA extraction. Information on genome-wide and epigenome-wide variation was assessed on the Illumina OMNI 2.5 million and Infinium HumanMethylation450 BeadChip arrays, respectively. This project may help to characterize the adverse environmental factors that are associated with the rate of cellular aging in the methylome and to discover new molecular pathways of traumatic-stress related disease. This will help to identify those individuals at greatest risk for accelerated agin and its negative health consequences. This is a necessary first step before risk factors can be modified with the ultimate aim of improving health.