Genome-Wide Association Study of Food Allergy

食物过敏（FA）是由免疫球蛋白（IG）E介导的对食物的超敏反应引起的病症，在美国和世界范围内是日益严重的临床和公共卫生问题。FA影响大约5-8%的儿童和1-4%的成人。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中起着重要作用。到目前为止，很少有遗传研究的FA已进行。该建议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。我们将使用正在进行的多中心FA研究的生物样本和流行病学及临床数据，采用标准方案。我们提出了一个两阶段的GWA研究。具体而言，Aim 1（第1阶段GWA研究）：我们将使用Illumina Human 1 M-Duo Infinium HD BeadChip对总计500名FA受影响的三人组（母亲、父亲和FA受影响的儿童，总计1，500名受试者）进行基因分型。我们将使用最好的统计方法测试每个SNP与FA的关联。我们将选择达到第1阶段显著性（p<10-4）的SNP以在第2阶段中进一步测试。目标2（第2阶段GWA研究）：我们将在另外500名FA受影响的三人组（母亲、父亲和FA受影响的儿童，共1,500名受试者）中对目标1中鉴定的所有有希望的SNP进行基因分型。我们将进行联合分析，将联合收割机结合1,000个三人组，共3,000名受试者。我们将在第2阶段使用全基因组显著性截止值（p<10-7）。这项研究将是第一个大规模的GWA研究的FA在美国鉴于我们有限的理解FA的病因和缺乏高度有利的候选基因的FA，GWA研究提供了最好的方法来解剖遗传基础的FA。本研究具有以下优势：（1）通过使用现有研究样本进行的高成本效益研究;（2）大样本量，确保有足够的统计能力来解决主要目标;（3）利用最先进的高通量基因分型技术和统计方法;以及（4）高度互动和经验丰富的多学科研究团队。我们期望这项研究将导致识别新的遗传位点的FA，这将铺平道路，为未来的调查。需要密集的后续工作，包括独立复制，精细定位，测序和功能研究，以进一步阐明哪些特定变体是因果关系，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。这项拟议的研究的一个特别的优势是，它提供了一个巨大的潜力，为未来的研究FA，鉴于完善的基础设施和资源。总的来说，这项研究和未来的研究将有助于开发一个有前途的模式，以确定个人在FA的高风险，并制定有效的战略，预防和治疗FA。

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.