Epigenome Association Study of Food Allergy

描述(由申请人提供)：食物过敏(FA)是一种由免疫球蛋白(Ig)E介导的对食物的超敏反应引起的疾病。FA影响大约5%-8%的儿童和1%-4%的成年人，在美国和世界范围内是一个日益严重的临床和公共卫生问题。预防和治疗FA的主要障碍是我们对其病因和生物学机制的了解不够深入。现有证据表明，FA是一个由多种环境和遗传因素决定的复杂性状。这一建议建立在我们正在进行的对FA的环境和遗传因素的调查基础上，并旨在探索一个新的领域：表观基因组与FA的关联。表观遗传学被定义为研究在不改变DNA序列的情况下发生的基因表达的可遗传变化。表观基因组学是在全基因组范围内对表观遗传学的研究。虽然还没有关于FA的表观遗传学或表观基因组学数据，但表观遗传学似乎在Th细胞分化和细胞因子基因表达方面发挥了重要作用。我们假设，临床、环境、遗传和表观遗传学数据的结合是理解FA病因学和生物学机制的一种有前途的方法，特别是这可能提供关于遗传变异和环境暴露如何改变FA的风险、严重性和长期结果的机械性见解。这项建议的中心焦点是进行全基因组作图，以确定FA的表观遗传变化，并将这些数据与表型、环境和遗传数据相结合。我们将利用芝加哥队列的广泛资源来解决以下具体目标：目标1A：我们将使用Illumina HumanMethylation27 DNA分析珠芯片(Infinium)，对600名白人儿童进行表观基因组图谱：来自芝加哥队列的300例牛奶过敏(CMA)病例和300例非过敏对照。在控制了潜在的重要协变量和混杂因素后，我们将检验这一假设，即静脉血样中的表观遗传学改变与CMA的风险相关。目的1B(探索性)：我们将比较无过敏史和有过敏史两组CMA病例的表观基因组模式。在控制了潜在的重要协变量和混杂因素后，我们将测试表观基因组模式因CMA严重程度而不同的假设。目标2(探索性)：我们将把表观基因组学数据与我们在芝加哥队列中获得的广泛的表型、环境和SNPs数据整合在一起，这使我们能够同时评估环境、遗传学和表观基因组学及其在CMA中的相互作用。这项拟议研究的结果可能会改变我们对FA的病因和生物学机制的理解。与遗传变异不同，表观遗传交替可能是可逆的。对表观遗传机制的更好理解可能会导致对FA的预测、预防和治疗的新范式的发展。在美国和全世界，食物过敏(FA)是一个日益严重的临床和公共卫生问题。预防和治疗FA的主要障碍是我们对其病因和生物学机制的了解不够深入。这项建议旨在进行全基因组作图，以确定FA的表观基因组改变，并将这些数据与临床、环境和遗传数据相结合。研究结果对制定预测、预防和治疗FA的策略具有重要意义。

DESCRIPTION (provided by applicant): Food allergy (FA) is a condition caused by an immunoglobulin (Ig) E-mediated hypersensitivity reaction to food. FA affects approximately 5-8% of children and 1-4% of adults and is a growing clinical and public health problem in the U.S. and worldwide. The major obstacle in preventing and treating FA has been our incomplete understanding of its etiology and biological mechanisms. Available evidence suggests that FA is a complex trait determined by multiple environmental and genetic factors. This proposal is built on our ongoing investigation of environmental and genetic factors of FA, and is designed to explore a novel area: epigenomic associations with FA. Epigenetics is defined as the study of heritable changes in gene expression that occur without changing DNA sequences. Epigenomics is the study of epigenetics on a genome-wide scale. While there is no epigenetic or epigenomic data available for FA, epigenetics appears to play an important role in Th cell differentiation and cytokine gene expression. We hypothesize that an integration of clinical, environmental, genetic and epigenetic data represents a promising approach to understand the etiology and biological mechanisms of FA, in particular, this may provide mechanistic insight into how genetic variants and environmental exposures can modify the risk, severity and long-term outcome of FA. The central focus of this proposal is to perform genome-wide mapping to identify epigenetic alterations in FA, and to integrate such data with phenotypic, environmental and genetic data. We will utilize the extensive resources of the Chicago Cohort to address the following specific aims: Aim 1A: We will conduct epigenomic mapping of 600 white children: 300 cow milk allergy (CMA) cases and 300 non-allergic controls from the Chicago Cohort, using the Illumina HumanMethylation27 DNA Analysis BeadChip (Infinium). We will test the hypothesis that epigenetic alterations in venous blood samples are associated with the risk of CMA, after controlling for potentially important covariates and confounders. Aim 1B (Exploratory): We will compare epigenomic patterns between two groups of CMA cases: without vs. with history of anaphylaxis. We will test the hypothesis that epigenomic patterns differ by severity of CMA, after controlling for potentially important covariates and confounders. Aim 2 (Exploratory): We will integrate epigenomic data with our extensive phenotypic, environmental and SNPs data available in the Chicago Cohort, which allow us to simultaneously evaluate the roles of environment, genetics, and epigenomics as well as their interactions in CMA. The findings from this proposed study may transform our understanding of the etiology and biological mechanisms of FA. Unlike genetic variants, epigenetic alternations are potentially reversible. A better understanding of epigenetic mechanisms may lead to the development of new paradigms for prediction, prevention and treatment of FA. Food allergy (FA) is a growing clinical and public health problem in the U.S. and worldwide. The major obstacle in preventing and treating FA has been our incomplete understanding of its etiology and biological mechanisms. This proposal aims to perform genome-wide mapping to identify epigenomic alterations in FA, and to integrate such data with clinical, environmental and genetic data. The study findings should have important implications for developing strategies in prediction, prevention and treatment of FA.