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（由申请人提供）：心理社会影响与影响人类健康的几种最常见疾病（心血管疾病、糖尿病、癌症）的病因有关。据推测，这些社会心理影响是通过基于 DNA 的生物变化（例如甲基化改变或端粒磨损）介导的。然而，由于该领域的研究很少，仍然存在许多问题：表观遗传和后天基因组变化在人类一生中积累到什么程度？童年时期的逆境是否会导致生物学上的变化，并持续到成年期？是否可以根据表观遗传、基因表达、端粒、染色体不稳定性和/或皮质醇水平特征，将童年时期经历过逆境的成年人确定为“有患疾病的风险”？为了回答这些问题，我们将研究 736 名双胞胎，他们在之前的研究中（2 至 15 年前完成）完成了严格的表型行为评估，并代表两个风险组：（1）经历过性虐待的极端童年逆境事件的双胞胎； (2) 双胞胎经历了广泛的社会经历。第 1 组（40-55 岁）将由 50 对童年性虐待史不一致的同卵双胞胎以及 50 对童年经历过性虐待（25 对）或未经历过性虐待（25 对）的同卵双胞胎组成。将在该队列的双胞胎之间测量和比较的生物学终点包括：（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) 染色体特异性端粒长度； (3) 获得性染色体不稳定的频率； (4) 基因表达模式； (4) 每日基础唾液皮质醇水平。第 2 组（20-30 岁）将由同卵双胞胎（157 对）和异卵双胞胎（111 对）的标准样本组成，这些双胞胎的行为表型在整个青春期到成年早期都经过仔细确定。从这些双胞胎的研究中获得的数据将提供有关多种逆境对内在生物变化的潜在累积影响的见解。该队列要测量的生物学终点（之前已采集了该队列的血样并且易于获得）包括：（1）使用基于阵列的方法进行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，将观察到的生物终点指标（双胞胎内部和之间）的变化与从人类生命周期的多个阶段收集的表型数据进行比较，将使我们能够推断出观察到的生物标志物差异在多大程度上受到童年逆境、成年逆境和/或其他环境压力因素的影响。这项调查的数据将首次直接估计成年人由于童年逆境而出现的表观遗传、端粒长度、获得性染色体不稳定性、基因表达和/或皮质醇水平变化的频率。 公共卫生相关性：环境和社会事件可能被生物“记住”，从而导致个人在多年后患上健康问题的风险增加，直到最近才被认识到。在这项研究中，我们将通过识别成人因不良（以及积极）童年事件而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调节因素。通过从我们独特的双胞胎群体中收集这些信息，其中包括选定的不一致同卵对样本，以及同卵双胞胎和异卵双胞胎的群体样本，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相关。这项研究收集的数据将建立生命早期压力对疾病的长期累积生物效应之间的关系。此外，从这项研究中获得的信息可用于开发生物标志物测定，以识别处于“患病风险”的个体，和/或导致开发治疗干预措施以减少不良健康结果。