Genetic Determinants of Food Allergy Among Pediatric Populations

描述(申请人提供)：食物过敏是一种复杂的公共卫生问题，影响约7%的儿科人口，是过敏反应的常见原因。食物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一半，每年导致美国约150人死亡。食物过敏是由食物蛋白引起的免疫不良反应引起的各种临床表现，其中最常见的食物过敏疾病是由食物特异性IgE抗体介导的疾病。花生过敏是大多数严重和致命的食物过敏反应的原因，花生过敏通常是终生的。虽然对IgE介导的食物过敏的遗传基础的研究非常有限，但遗传度研究和几项候选基因研究表明，与哮喘、变应性鼻炎(AR)和特应性皮炎(AD)这三种特应性疾病类似，对IgE介导的食物过敏的易感性可能是由多个基因决定的，基因-基因和基因-环境相互作用对食物过敏的影响有大有小。食物过敏和哮喘、AR和AD的高发病率表明，一些基因决定因素可能普遍赋予所有这四个特征风险。我们假设，有一些遗传决定因素是食物过敏所特有的，与那些与特应性疾病相关的基因座不同。我们进一步假设，某些基因决定因素与对特定食物(例如花生过敏)的特定免疫反应有关。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，以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强大的DNA储存库。这一队列与PI实验室现有的哮喘、特应性和AD数据集相结合，为食物过敏的基因研究提供了一个理想的机会。全基因组关联方法已被证明在阐明复杂性状的可靠候选基因方面是可行和有用的，特别是那些关于候选基因或座位的先验知识有限的候选基因。通过筛选代表整个基因组的密集标记小组，将识别出比传统的、基于候选基因的研究更多的风险变异。在这项探索性/发展性研究R21拨款申请中，我们将(1)通过建立一个包含2,000个欧洲和非洲血统患者样本的DNA库，为未来基于病例对照的、全基因组范围的关于IgE介导的一般食物过敏特别是花生过敏的研究奠定基础；以及(2)进行食物过敏易感性与有限的食物过敏候选基因之间的探索性遗传关联研究。这一申请的成功将为一项关于食物过敏的全基因组关联研究的更大规模的赠款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.