Epigenetic, Telomere & Chromosome Changes in Adult Twins Having Child Adversity

表观遗传、端粒

• 批准号: 8136597
• 负责人: COLLEEN K JACKSON-COOK
• 金额: $ 7.21万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136597
• 关键词: 8 year old; Adolescence; Adult; Adverse event; Age; Area; Base Sequence; Behavioral; Biological; Biological Assay; Biological Markers; Blood specimen; Cardiovascular Diseases; Cardiovascular system; Child; Child Sexual Abuse; Childhood; Chromosomal Instability; Chromosomes; Chromosomes, Human, Pair 2; Communicable Diseases; Coupling; DNA; Data; Databases; Development; Diabetes Mellitus; Disease; Dizygotic Twins; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Etiology; Evaluation; Event; Frequencies; Gene Expression; Gene Expression Alteration; Genetic Variation; Genomics; Goals; Health; Heritability; Human; Hydrocortisone; Illness impact; Individual; Investigation; Lead; Length; Life Stress; Location; Longevity; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Memory; Methodology; Methods; Methylation; Monozygotic Twinning; Monozygotic twins; Morbidity - disease rate; Mutation; Outcome; Pathologic; Pattern; Phenotype; Population; Psychosocial Influences; Recording of previous events; Research; Research Personnel; Risk; Risk Factors; Salivary; Sampling; Severities; Sexual abuse; Source; Staging; Therapeutic Intervention; Treatment/Psychosocial Effects; Twin Multiple Birth; Twin Studies; Violence; age related; base; behavioral health; cohort; environmental stressor; epigenomics; experience; genome-wide; insight; meetings; mortality; neglect; population based; public health relevance; respiratory; response; social; telomere; young adult

DESCRIPTION (provided by applicant): Psychosocial influences have been implicated in the etiology of several of the most common illnesses impacting human health (cardiovascular disease; diabetes; cancer). It has been hypothesized that these psychosocial effects are mediated through DNA-based biological changes, such as methylation alterations or telomere attrition. However, due to the paucity of research in this area, many questions remain: To what extent do epigenetic and acquired genomic changes accumulate over the human lifespan? Do childhood adversities result in biological changes that persist into adulthood? Can an adult who was exposed to childhood adversities be identified as "at risk" for developing disease based on their epigenetic, gene expression, telomeric, chromosomal instability, and/or cortisol level profiles? To answer these questions we will study 736 twins who have completed intense phenotypic behavioral evaluations in previous studies (completed 2 to 15 years ago) and represent two risks groups: (1) twins experiencing the extreme childhood adversity event of sexual abuse; and (2) twins experiencing a broad spectrum of social experiences. Cohort 1 (ages 40-55) will comprise a selected sample of 50 identical twin pairs who are discordant for a history of childhood sexual abuse, as well as 50 identical concordant pairs who did (25 pairs) or did not (25 pairs) experience sexual abuse as a child. The biological endpoints that will be measured and compared between co-twins for this cohort include: (1) frequencies and locations of genome-wide methylation changes using a sequence-based approach; (2) chromosome-specific telomere lengths; (3) frequencies of acquired chromosomal instability; (4) patterns of gene expression; and (4) diurnal basal salivary cortisol levels. Cohort 2 (ages 20-30) will be comprised of a normative sample of monozygotic (157 pairs) and dizygotic (111 pairs) twin pairs for whom behavioral phenotypes have been carefully determined throughout adolescence into young adulthood. The data gained from the study of these twins will provide insight as to the potential cumulative effect of multiple adversities on embedded biological changes. The biological endpoints to be measured for this cohort (for whom blood samples have been previously collected and are readily available) include: (1) frequencies and locations of genome-wide methylation changes using array based methodology; and (2) gene expression patterns. Collectively, comparisons of observed alterations in biological endpoint measures (within and between twins) to phenotypic data collected from multiple stages in the human lifespan will allow us to deduce the extent to which the observed differences in biomarkers are influenced by childhood adversity, adult adversity, and/or other environmental stressors. The data from this investigation will lead to the first direct estimate of the frequency of epigenetic, telomere length, acquired chromosomal instability, gene expression, and/or cortisol level changes that arise in adults due to childhood adversities. PUBLIC HEALTH RELEVANCE: The potential that environmental and social events can be biologically "remembered" to result in an individual having an increased risk for developing health conditions many years later has only recently been recognized. In this study we will identify potential mediators of this biological memory by recognizing changes in genomic and epigenomic patterns that are acquired in adults as a result of adverse (as well as positive) childhood events. By collecting this information from our unique population of twins, which includes a selected sample of discordant identical pairs, as well as a population sample of identical and fraternal twins, we can determine if observed behavioral and health outcomes are associated with specific genetic or epigenetic changes. The data collected from this study will establish a relationship between the long-term, cumulative biological effects of early-life stresses on disease. Moreover, the information gained from this study could be exploited to develop a biomarker assay to recognize individuals who are at "at risk" for acquiring illnesses, and/or lead to the development of therapeutic interventions to reduce adverse health outcomes.

描述（申请人提供）：心理社会影响与影响人类健康的几种最常见疾病的病因有关（心血管疾病；糖尿病；癌症）。假设这些社会心理效应是通过基于DNA的生物学变化（例如甲基化改变或端粒损耗）介导的。但是，由于该领域的研究很少，因此仍然存在许多问题：表观遗传和获得的基因组变化在人类寿命中积累了多大程度？童年逆境会导致成年的生物学变化吗？暴露于童年逆境的成年人是否可以根据其表观遗传学，基因表达，端粒，染色体不稳定性和/或皮质醇水平的特征来确定患病的“风险”？为了回答这些问题，我们将研究736个双胞胎，他们在先前的研究中完成了激烈的表型行为评估（完成了2至15年前），并代表了两个风险群体：（1）经历过极端童年遭受性虐待事件的双胞胎； （2）双胞胎经历了各种各样的社会经验。队列1（40-55岁）将包括一个对童年性虐待史的50对相同双胞胎对的样本，以及50对相同的一致对，他们（25对）或没有（25对）（25对）从小就经历性虐待。该队列的共晶型二线将测量和比较的生物终点包括：（1）使用基于序列的方法，全基因组甲基化变化的频率和位置； （2）特定于染色体的端粒长度； （3）获得的染色体不稳定性的频率； （4）基因表达的模式； （4）昼夜唾液皮质醇水平。队列2（20-30岁）将由单一粘液（157对）的规范性样本和双胞胎（111对）双胞胎对组成。从这些双胞胎的研究中获得的数据将提供有关多个逆境对嵌入生物学变化的潜在累积影响的见解。为该队列测量的生物终点（先前已收集了血液样本并容易获得）包括：（1）使用基于阵列的方法论，全基因组甲基化变化的频率和位置； （2）基因表达模式。总的来说，观察到的生物学终点测量方法（双胞胎内部和之间）与从人类寿命的多个阶段收集的表型数据的变化的比较将使我们能够推断出观察到的生物标志物差异受儿童逆境，成人逆境和/或其他环境压力影响的程度。这项研究的数据将导致对表观遗传学，端粒长度，获得的染色体不稳定性，基因表达和/或皮质醇水平变化的频率的首次直接估计。 公共卫生相关性：在生物学上可以“记住”环境和社交事件的潜力，从而导致一个人在多年以后患健康状况的风险增加，直到最近才被认可。在这项研究中，我们将通过识别由于不良（以及积极的儿童事件）而在成年人中获得的基因组和表观基因组模式的变化来确定这种生物记忆的潜在介体。通过从我们独特的双胞胎人群中收集这些信息，其中包括选定的不一致对对样本，以及相同和兄弟双胞胎的种群样本，我们可以确定观察到的行为和健康结果是否与特定的遗传或表观遗传变化有关。从这项研究中收集的数据将建立早期应激对疾病的长期生物学作用之间的关系。此外，可以利用从这项研究中获得的信息开发生物标志物测定法，以识别患有疾病的“有风险”的人，和/或导致制定治疗干预措施以减少不良健康结果。