Epigenome-wide Association Study of Preterm Birth

描述(申请人提供)：早产(PTB)，通常定义为怀孕37周前分娩的婴儿，在美国影响12.6%的新生儿。预防和治疗早产的一个主要障碍是我们对其病因和生物学机制的不完全了解。文献和我们的工作都提供了令人信服的证据，表明肺结核受到环境和遗传因素及其相互作用的影响。到目前为止，结核病的研究在很大程度上忽略了表观基因组学，表观基因组学将发育过程中核重新编程的机制与环境诱导的生物变化以及细胞对外部刺激的反应能力统一起来。这项建议的中心焦点是在个体遗传易感性和环境暴露的背景下确定表观基因组的变化，并获得对基因组、表观基因组和环境因素影响肺结核风险的生物学机制的重要洞察。我们建议实现以下目标。目的1：我们将对500名非裔美国母亲进行表观基因组图谱，其中包括250名自发的极早产病例和250名来自现有波士顿出生队列的足月正常出生体重对照。我们将使用Illumina Human Methylation27DNA分析芯片进行表观基因组图谱。我们将检验这样一种假设，即出生时获得的孕妇静脉血样本中DNA甲基化的变化与肺结核的风险有关。目的2：我们将使用相同的Illumina平台，对目标1中母亲所生的500名婴儿进行表观基因组图谱绘制。我们将检验这样一种假设，即出生时获得的脐带血样本中DNA甲基化的改变与肺结核的风险有关。探索性分析：我们将利用波士顿出生队列的广泛数据库，同时评估环境、基因组和表观基因组因素在肺结核中的作用及其相互作用。我们还将探讨母体和胎儿表观基因组与肺结核的相互作用。这将是第一次在非裔美国人母婴配对中进行肺结核的表观基因组学研究，这对非裔美国人母婴配对是一个社会环境逆境发生率高、肺结核风险高的人群。这一建议有许多独特之处，包括利用现有的精心设计和良好表型的出生队列进行的高成本效益研究；在结核病中整合环境、基因组和表观基因组因素的创新方法；以及高度互动和经验丰富的多学科研究团队，其合作和生产力记录良好。这项研究对改变我们对肺结核的病因和生物学机制的认识具有很大的潜力，特别是在城市内的高危少数民族人群中，这将对降低美国肺结核的发病率和缩小早产差距具有关键意义。 公共卫生相关性：在美国，每年每八个活产婴儿中就有一个以上是早产儿(PTB)。肺结核是婴儿发病率和死亡率的主要原因，并与各种短期和长期健康和发育问题的风险增加有关。这项建议的中心焦点是确定与肺结核相关的母体和胎儿表观基因组改变。这项研究的发现将有助于深入了解基因组、表观基因组和环境因素如何影响肺结核的风险。

DESCRIPTION (provided by applicant): Preterm Birth (PTB), commonly defined as delivery of an infant before 37 weeks of gestation, affects 12.6% of all births in the U.S. A major obstacle in preventing and treating PTB has been our incomplete understanding of its etiology and biological mechanisms. Both the literature and our work have provided compelling evidence that PTB is influenced by environmental and genetic factors and their interactions. To date, PTB research has largely omitted epigenomics, which unites mechanisms of nuclear reprogramming during development with environmentally induced biological changes, and the ability of cells to respond to external stimuli. The central focus of this proposal is to identify epigenomic alterations in the context of individual genetic susceptibility and environmental exposures and to gain important insight into the biological mechanisms by which genomic, epigenomic, and environmental factors affect the risk of PTB. We propose to accomplish the following aims. Aim 1: We will conduct epigenomic mapping among 500 African American mothers, including 250 spontaneous very preterm cases and 250 term, normal birth weight controls drawn from the existent Boston Birth Cohort. We will use the Illumina HumanMethylation27 DNA Analysis BeadChip for epigenomic mapping. We will test the hypothesis that alterations of DNA methylation in maternal venous blood samples obtained at birth are associated with the risk of PTB. Aim 2: We will conduct epigenomic mapping among 500 infants born to the mothers included in Aim 1, using the same Illumina platform. We will test the hypothesis that alterations of DNA methylation in cord blood samples obtained at birth are associated with the risk of PTB. Exploratory Analysis: We will utilize the extensive database of the Boston Birth Cohort to simultaneously evaluate the roles of environment, genomic, and epigenomic factors as well as their interactions in PTB. We will also explore the interplay of maternal and fetal epigenome in relation to PTB. This will be the first epigenomic study of PTB in conjunction with GWAS in African American mother-infant pairs, a population with high prevalence of socio-environmental adversities and high risk of PTB. This proposal has many unique features, including a highly cost-efficient study by using an existent well-designed and well-phenotyped birth cohort; an innovative approach to integrate environment, genomic and epigenomic factors in PTB; and a highly interactive and experienced multidisciplinary research team with a track record of collaboration and productivity. This proposed study has a great potential to transform our understanding of the etiology and biological mechanisms of PTB, especially, among high risk inner-city minority populations, which will be of key importance for lowering the incidence of PTB and reducing preterm disparity in the U.S. PUBLIC HEALTH RELEVANCE: In the U.S, more than one out of every eight live births is premature infants (PTB) each year. PTB is a major cause of infant morbidity and mortality and is associated with increased risk for a wide range of short- and long-term health and developmental problems. The central focus of this proposal is to identify maternal and fetal epigenomic alterations in relation to PTB. Findings from this study will help gain important insight into how genomic, epigenomic, and environmental factors affect the risk of PTB.