Genetic Determinants of Food Allergy Among Pediatric Populations

描述（由申请方提供）：食物过敏是一种具有重大公共卫生问题的复杂疾病，影响约7%的儿科人群，是过敏反应的常见原因。食物引起的过敏反应的患病率正在上升，占全球过敏反应病例的三分之一到二分之一，每年在美国导致约150人死亡。食物变态反应代表归因于对食物蛋白质的不良免疫应答的多种临床表现，其中最常见的食物变态反应性病症是由食物特异性IgE抗体介导的那些。花生过敏占严重和致命食物过敏反应的大多数，而且对花生的过敏通常是终生的。尽管关注IgE介导的食物过敏的遗传基础的研究受到严重限制，但遗传性研究和几个候选基因研究表明，与哮喘、过敏性鼻炎（AR）和特应性皮炎（AD）的“特应性三联体”疾病相似，IgE介导的食物过敏的易感性可能由多个基因决定，其主要和次要影响受基因-基因和基因-环境相互作用的影响。食物过敏与哮喘、AR和AD之间的高共病率表明，某些遗传决定因素可能会普遍赋予所有四种特征的风险。我们假设，有遗传决定因素，这是独特的食物过敏和不同的基因座与特应性。我们进一步假设，某些遗传决定因素与对特定食物的特定免疫反应有关（例如，花生过敏）。食物过敏研究联盟（CoFAR）的一个主要目标是收集食物过敏婴儿的生物样本和广泛的表型数据，旨在跟踪花生过敏的发展;因此，该计划提供了一个独特的机会，为广泛的遗传流行病学研究建立一个强大的DNA库。该队列，结合PI实验室中现有的哮喘、特应性和AD数据集，为食物过敏的遗传研究提供了理想的机会。全基因组关联的方法已被证明是可行的和有用的，阐明坚实的候选基因的复杂性状，特别是那些有有限的先验知识的候选基因或位点。通过筛选代表整个基因组的标记密集组，将比使用传统的候选基因研究所能实现的更多的风险变体。在这项探索性/发展性研究R21资助申请中，我们将（1）通过建立一个包含2,000份欧洲和非洲裔患者样本的DNA储存库，为未来基于病例对照的全基因组关联研究建立基础设施，该研究涉及IgE介导的食物过敏，特别是花生过敏;以及（2）进行食物过敏易感性与食物过敏的有限候选基因集之间的探索性遗传关联研究。这项申请的成功将为更大规模的食物过敏全基因组关联研究申请提供必要的初步数据和基础设施。

DESCRIPTION (provided by applicant): Food allergy is a complex disease of substantial public health concern, affecting ~7% of the pediatric population, and is a common cause of anaphylaxis. The prevalence of food-induced anaphylaxis is rising, accounting for one-third to one-half of anaphylaxis cases globally and resulting in ~150 deaths in the U.S. annually. Food allergy represents a variety of clinical manifestations attributed to adverse immunologic responses to food proteins, with the most common of food allergic disorders being those mediated by food-specific IgE antibodies. Peanut allergy accounts for the majority of severe and deadly food allergic reactions, and allergies to peanut are typically life-long. Although studies focusing on the genetic basis for IgE-mediated food allergy have been seriously limited, heritability studies and several candidate gene studies suggest that, similar to the 'atopic triad' diseases of asthma, allergic rhinitis (AR), and atopic dermatitis (AD), susceptibility to IgE-mediated food allergy is likely determined by multiple genes with major and minor influences impacted by gene-gene and gene-environment interactions. The high rate of co-morbidity between food allergy and asthma, AR and AD suggests that some genetic determinants may generically confer risk to all four traits. We hypothesize that there are genetic determinants which are unique to food allergy and distinct from those loci associated with atopy. We further hypothesize that certain genetic determinants are associated with a specific immune response to specific foods (e.g., peanut allergy). A major goal of the Consortium of Food Allergy Research (CoFAR) is to collect biological samples and extensive phenotypic data on food allergic infants with an aim to track the development of peanut allergy; thus, this program offers a unique opportunity to establish a robust DNA repository for extensive genetic epidemiology studies. This cohort, combined with existing datasets of asthma, atopy, and AD in the PI's laboratory, renders an ideal opportunity for genetic studies on food allergy. The genome-wide association approach has proved to be both feasible and useful in terms of elucidating solid candidate genes for complex traits, especially those for which there is limited a priori knowledge regarding candidate genes or loci. By screening dense panels of markers representing the entire genome, many more risk variants will be identified than what could be accomplished using conventional, candidate gene-based studies. In this Exploratory/Developmental Research R21 Grant application, we will (1) develop the research infrastructure for a future case-control-based, genome-wide association study on IgE-mediated food allergy in general and peanut allergy in particular, by establishing a DNA repository of 2,000 samples from patients of European and African descent; and (2) perform exploratory genetic association studies between food allergy susceptibility and a limited set of candidate genes for food allergy. Success in this application will provide the essential preliminary data and infrastructure for a larger grant application for a genome-wide association study on food allergy.