Statistical Methods for Epigenetic Mediation of Exposure-response Relations

暴露-反应关系表观遗传调节的统计方法

• 批准号: 8219246
• 负责人: Duncan C. Thomas
• 金额: $ 16.35万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-18 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8219246
• 关键词: Accounting; Address; Affect; Air Pollution; Biological Assay; Blood; Candidate Disease Gene; Cells; Child; Child health care; Childhood Asthma; Chronic; Cohort Studies; Complex; Computer Simulation; Constitutional; Controlled Study; CpG Islands; DNA; DNA Methylation; DNA Sequence; Data; Dietary Supplementation; Disease; Environmental Exposure; Environmental Risk Factor; Environmental Tobacco Smoke; Epidemiology; Epigenetic Process; Event; Exposure to; Family; Functional RNA; Gene Expression; Gene Expression Alteration; Gene Mutation; Generations; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Health; Histones; Individual; Intervention; Measurement; Mediating; Mediation; Mediator of activation protein; Methodology; Methods; Methylation; Modeling; Motivation; National Children' s Study; Neonatal; Outcome; Parents; Participant; Performance; Play; Process; Promoter Regions; Recording of previous events; Research Personnel; Risk; Role; Schools; Smoking; Spottings; Statistical Methods; Testing; Time; Tobacco smoking; Variant; disorder risk; flexibility; grandparent; histone modification; in utero; innovation; longitudinal analysis; offspring; population based; prenatal exposure; response; tool; trait; transmission process

DESCRIPTION (provided by applicant): It is now well established that epigenetic phenomena such as DNA methylation and histone modifications play an important role in gene expression, and alterations in epigenetic states can affect the risk of many diseases. The role of environmental factors, constitutional genotype, and their interactions in determining epigenetic states has been less well studied, however, particularly the potential for epigenetics to serve as a mediator between environmental exposures and disease. Several lines of evidence also suggest that certain environmental exposures can have effects on health outcomes in subsequent generations. This proposal has two broad methodological aims, to develop statistical methods (1) to assess the role of epigenetics in mediating exposure-response relationships within an individual, and (2) to assess its role in mediating transgenerational effects of exposure. For the first of these we will (aim 1a) develop a flexible measurement error framework that can accommodate variation in exposure and methylation over time and relate it to a variety of types of outcomes (binary, continuous, longitudinal, censored time-to-event) and (aim 1b) develop ways of summarizing complex methylation profiles and relating these profiles to both determinants of epigenetic status (environmental and genetic) and to the risk of disease. For the second aim, we will develop a variant of the transmission-disequilibrium test, extending genotypes at a given locus to include epigenetic mark, allowing for transmission of these marks from either parent in a non-Mendelian fashion. The methylation status of parents and offspring will be treated as latent variables that are functions of their own and/or their respective parents' exposures. The statistical performance of these methods will be studied by computer simulation. We will apply these methods to various subsets of participants in the Children's Health Study (CHS) - a long-term cohort study of the chronic effects of air pollution and other exposures like in utero and environmental tobacco smoke in 12,000 school children - for whom DNA are available for global and locus- specific methylation assays; these include neonatal blood spot and later buccal cells for the longitudinal analysis in aim 1 and complete trios with grandmaternal smoking data for aim 2. Our goal is to develop generalizable methodology that will be broadly applicable to studies of environmental epigenetics, using data from the CHS simply as motivation and illustration. For example, we anticipate that these methods could be useful for the analysis of epigenetic data from three-generation subsamples from the National Children's Study. PUBLIC HEALTH RELEVANCE: Epigenetics refers to various changes that can affect the expression of genes without altering their underlying DNA sequence, including DNA methylation, histone alterations, small non-coding RNAs, etc. Despite abundant evidence of their role in many disease processes, the environmental determinants of these epigenetic changes have not been as well studied and little is little known about their role in mediating exposure-response relationships or transmission of exposure effects across generations. This project aims to develop innovative statistical methods to provide epidemiologic investigators with tools for addressing these questions. Unlike DNA mutations, epigenetic changes are potentially reversible, for example, through dietary supplementation with methyl donors or other agents, opening the possibility for population-based interventions to protect against adverse environmental exposures.

描述（由申请人提供）：现在已经很好地确定表观遗传现象（例如DNA甲基化和组蛋白修饰）在基因表达中起重要作用，并且表观遗传状态的改变会影响许多疾病的风险。然而，对环境因素，宪法基因型及其相互作用在确定表观遗传状态的作用的研究较少，尤其是表观遗传学作为环境暴露和疾病之间的介体的潜力。几条证据还表明，某些环境暴露会对随后的几代人产生影响。该提案具有两个广泛的方法论目的，以开发统计方法（1）评估表观遗传学在介导个人内的暴露反应关系中的作用，以及（2）评估其在介导暴露传播跨代作用中的作用。 For the first of these we will (aim 1a) develop a flexible measurement error framework that can accommodate variation in exposure and methylation over time and relate it to a variety of types of outcomes (binary, continuous, longitudinal, censored time-to-event) and (aim 1b) develop ways of summarizing complex methylation profiles and relating these profiles to both determinants of epigenetic status (environmental and genetic) and to the risk of 疾病。为了第二个目标，我们将开发传输二级试验测试的变体，从而在给定的基因座上扩展基因型以包括表观遗传标记，从而可以以非孟德尔时尚的方式从任一个父母那里传递这些标记。父母和后代的甲基化状况将被视为其自身和/或各自父母暴露的功能的潜在变量。这些方法的统计性能将通过计算机模拟研究。我们将将这些方法应用于儿童健康研究（CHS）的各种参与者的子集 - 一项长期队列研究，对12,000名儿童中的空气污染和其他暴露（例如子宫和环境烟草烟雾）的慢性影响 - 为全球和局部特异性甲基化鉴定提供DNA；其中包括新生儿血液点和后来的颊细胞，用于在AIM 1中进行纵向分析，并使用AIM 2的宏伟吸烟数据进行完整的三重奏。我们的目标是使用CHS的动机和插图中的数据开发可广泛适用于环境表观遗传学的可广义方法。例如，我们预计这些方法可能对来自国家儿童研究的三代子样本的表观遗传数据有用。 公共卫生相关性：表观遗传学是指可能影响基因表达的各种变化，而不会改变其潜在的DNA序列，包括DNA甲基化，组蛋白改变，小型非编码RNA等。尽管证据表明其在许多疾病过程中的作用，但这些表观遗传变化的影响却几乎没有涉及在许多疾病过程中的作用，并且在这些疾病过程中的影响却几乎没有 - 在这些疾病过程中的影响以及在这些疾病过程中的影响，并且在这些疾病过程中的作用却差异很大。几代人。该项目旨在开发创新的统计方法，为流行病学研究人员提供解决这些问题的工具。与DNA突变不同，表观遗传变化可能是可逆的，例如，通过补充甲基供体或其他药物的饮食，为预防不良环境暴露的基于人群的干预措施打开了可能性。