Prenatal Tobacco Smoke, Genetic and Epigenetic Changes, and Respiratory Health

描述（由申请人提供）：哮喘是儿童发病的主要原因，正常的肺功能发育对儿童和成年后的呼吸健康至关重要。我们已经开发了初步数据，强调产前烟草烟雾（PTS）暴露的不利影响。PTS暴露可永久性地改变发育中的肺和胎儿免疫功能，增加呼吸道疾病的风险，了解这些影响的机制可能有助于了解其他环境暴露的影响。科学家们已经清楚地证明，早期生活环境和遗传因素都有助于哮喘和肺功能的发病机制。最近的研究强调了遗传变异和表观遗传改变在环境相关免疫功能和呼吸健康中的重要性。我们的初步研究表明，在PTS的早期肺功能和哮喘发病机制中，I型受体酪氨酸激酶TAM （TYRO3， AXL和MER）家族的遗传和表观遗传变异具有潜在的重要性。为了提供一个有助于解决这一关键知识缺口的概念框架，我们提出对I型受体酪氨酸激酶的TAM （TYRO3， AXL和MER）家族进行综合表观遗传学分析，以更好地了解肺功能发育受损和与PTS相关的哮喘风险增加的生物学机制。具体来说，这个应用程序建立在PI的K01项目的基础上，进一步评估儿童健康研究（CHS）中的1500名受试者，这是一项对南加州16个社区的空气污染物和呼吸系统健康的纵向研究。这项研究将利用现有的综合资源，包括全基因组关联数据、相关出生记录和广泛的呼吸评估。该项目将重点放在TAM基因家族进行拟议的综合分析，因为这些基因在慢性炎症和自身免疫性疾病的发展中很重要，我们的初步数据表明表观遗传机制可能起作用。该提案将实现以下目标：(1)表征PTS暴露与TAM基因DNA甲基化之间的关联，并验证观察到的关联；(2)探究单倍型是否与TAM基因DNA甲基化相关或修饰pts相关DNA甲基化；(3)表征PTS暴露与mi-R34a和miR-199a/b启动子DNA甲基化水平之间的关系，这是已知的调节AXL表达的三种mirna，并进一步与它们的表达水平相关；(4)使用基于典型相关的方法，构建PTS暴露、CpG甲基化、基因或miRNA表达以及与哮喘和肺功能相关的TAM基因单倍型之间相互关系的综合图谱。我们提出的综合表观遗传分析结合新生儿血斑（NBS）的新方法来测量产前暴露和表观遗传改变，有望为研究具有早期环境起源的各种复杂人类疾病的表观遗传机制提供一种强有力的方法。

DESCRIPTION (provided by applicant): Asthma is a leading cause of childhood morbidity and normal lung function development is essential for respiratory health during childhood and subsequent adult life. We have developed preliminary data that highlight the adverse effects of prenatal tobacco smoke (PTS) exposure. PTS exposure can permanently alter the developing lung and fetal immune function, increasing risk for respiratory disease, and understanding the mechanisms of these effects may shed light on the effects of other environmental exposures. Scientists have clearly demonstrated both early-life environmental and genetic factors contribute to the pathogenesis of asthma and lung function. Recent studies highlight the importance of genetic variants and epigenetic alterations underlying environmentally-related immune function and respiratory health. We present preliminary studies showing the potential importance of genetic and epigenetic variation in the TAM (TYRO3, AXL, and MER) family of Type I receptor tyrosine kinases in early life lung function and asthma pathogenesis in the context of PTS. To provide a conceptual framework useful for addressing this critical knowledge gap, we propose an integrated epigenetic-genetic analysis of the TAM (TYRO3, AXL, and MER) family of Type I receptor tyrosine kinases to better understand the biological mechanisms underlying the impaired lung function development and increased risk of asthma associated with PTS. Specifically, this application builds on the PI's K01 project to further evaluate 1500 subjects in the Children's Health Study (CHS), a longitudinal study of air pollutant and respiratory health in 16 Southern California communities. The study will leverage an existing comprehensive resource that includes genome-wide association data, linked birth records, and extensive respiratory assessments. The project focuses on the TAM gene family for the proposed integrated analysis because these genes are important in the development of chronic inflammatory and autoimmune diseases and our preliminary data suggest epigenetic mechanisms may play a role. The proposal will accomplish the following aims: (1) characterize the association between PTS exposure and TAM gene DNA methylation and validate observed associations; (2) explore whether haplotypes are associated with TAM gene DNA methylation or modify the PTS-associated DNA methylation; (3) characterize the association between PTS exposure and promoter DNA methylation of mi-R34a and miR-199a/b levels, three miRNAs known to regulate AXL expression, and further relate to their expression levels; and (4) build a comprehensive picture of the inter- relationships between PTS exposure, CpG methylation, gene or miRNA expression, and haplotypes in the TAM genes in association with asthma and lung function using methods based on canonical correlation. The proposed integrated epigenetic-genetic analysis coupled with the novel use of newborn bloodspots (NBS) to measure prenatal exposure and epigenetic alterations is expected to offer a powerful approach to studying the epigenetic-genetic mechanism for various complex human diseases with early-life environmental origins.]