Genome-Wide Association Study of Food Allergy

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，在美国和全世界都是一个日益严重的临床和公共卫生问题。大约有5-8%的儿童和1-4%的成年人患有FA。阳性家族史是公认的过敏性疾病的预测因子。我们的初步数据强烈表明遗传因素在FA中起重要作用。迄今为止，FA的遗传研究很少。本提案的中心焦点是进行全基因组关联（GWA）研究，以确定FA的易感基因。我们将使用标准方案，利用正在进行的多中心FA研究的生物样本、流行病学和临床数据。我们建议进行两阶段的GWA研究。具体来说，Aim1（第一阶段GWA研究）：我们将使用Illumina Human1M-Duo Infinium HD BeadChip对总共500名FA影响的三人组（母亲、父亲和FA影响的孩子，共1500名受试者）进行基因分型。我们将使用最佳的统计方法测试每个SNP与FA的关联。我们将选择达到第一阶段显著性（p<10-4）的snp在第二阶段进一步测试。目的2（2期GWA研究）：我们将在另外500个FA影响的三人组（母亲、父亲和FA影响的孩子，共1500名受试者）中，对从目的1中发现的所有有希望的snp进行基因分型。我们将进行联合分析，将1000个三重奏组合在一起，总共3000个主题。我们将在第二阶段使用全基因组显著性截止值（p<10-7）。鉴于我们对FA病因的了解有限，且缺乏高度有利的FA候选基因，这项研究将是美国首次大规模的FA GWA研究，GWA研究提供了最佳的方法来解剖FA的遗传基础。本研究具有以下优势：(1)利用现有研究样本进行成本效益高的研究；（二）样本量大，保证有足够的统计能力来解决主要问题；(3)利用最新的高通量基因分型技术和统计方法；(4)一支高度互动、经验丰富的多学科研究团队。我们期望通过本研究能够鉴定出FA新的遗传位点，为今后的研究铺平道路。需要深入的后续工作，包括独立的复制、精细的制图、测序和功能研究，以进一步阐明哪些特定的变异是因果关系，生物学机制是什么，以及它们如何与其他遗传或环境因素相互作用。这项研究的一个特别优势是，鉴于完善的基础设施和资源，它为未来的FA研究提供了巨大的潜力。总的来说，这项研究和未来的研究将有助于建立一个有希望的范例，以识别FA的高风险个体，并制定有效的预防和治疗FA的策略。

Food allergy (FA), a condition caused by an immunoglobulin (Ig) E-mediated hypersensitivity reaction to food, is a growing clinical and public health problem in the U.S. and worldwide. FA affects approximately 5-8% children and 1-4% of adults. A positive family history is a well-recognized predictor of allergic diseases. Our preliminary data strongly suggest that genetic factors play an important role in FA. To date, few genetic studies of FA have been conducted. The central focus of this proposal is to conduct a genome-wide association (GWA) study to identify susceptibility genes for FA. We will utilize biological samples and epidemiological and clinical data from our ongoing multi-center FA study using a standard protocol. We propose a two-stage GWA study. Specifically, Aim1 (Stage 1 GWA study): We will genotype a total of 500 FA affected trios (mother, father, and FA affected child, a total of 1,500 subjects), using the Illumina Human1M-Duo Infinium HD BeadChip. We will test each SNP for association with FA using best available statistical methods. We will select SNPs reaching Stage 1 significance (p<10-4) to be further tested in Stage 2. Aim2 (Stage 2 GWA study): We will genotype all the promising SNPs identified from Aim 1 in another 500 FA affected trios (mother, father, and FA affected child, a total of 1,500 subjects). We will perform joint analysis that will combine the 1,000 trios, a total of 3,000 subjects. We will use the genome-wide significance cutoff (p<10-7) in Stage 2. This study will be the first large-scale GWA study of FA in the U.S. Given our limited understanding of the etiology of FA and lack of highly favorable candidate genes of FA, a GWA study offers the best available approach to dissect genetic basis of FA. This study has the following strength: (1) a highly cost-efficient study by using existing study samples; (2) a large sample size that assures adequate statistical power for addressing the primary aims; (3) utilization of state-of-the-art, high-throughput genotyping technology and statistical methods; and (4) a highly interactive and experienced multidisciplinary research team. We anticipate that this study will lead to identification of novel genetic loci of FA, which will pave the road for the future investigation. Intensive follow-up work, including independent replications, fine mapping, sequencing, and functional studies, is required to further elucidate which specific variants are causal, what are the biological mechanisms, and how they interact with other genetic or environmental factors. A particular strength of this proposed study is that it offers a tremendous potential for future studies of FA, given the well-established infrastructure and resources. Collectively, this and future studies will help develop a promising paradigm for identifying individuals at high risk of FA, and developing effective strategies for prevention and treatment of FA.