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，在美国和世界范围内是一个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%的成年人。阳性家族史是公认的过敏性疾病的预测因子。我们的初步数据有力地表明遗传因素在FA中起着重要作用。到目前为止，对FA的遗传学研究还很少。这项提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。我们将利用我们正在进行的多中心FA研究的生物样本以及流行病学和临床数据，使用标准方案。我们提出了一项分两个阶段的GWA研究。具体来说，Aim1(阶段1 GWA研究)：我们将使用Illumina Human1M-Duo Infinium HD BeadChip对总共500个FA影响的三人组(母亲、父亲和FA影响的孩子，总共1500个受试者)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。我们将选择达到阶段1显着性的SNPs(p&lt；10-4)在阶段2进行进一步测试。AIM2(阶段2 GWA研究)：我们将在另外500个FA影响的三个组(母亲、父亲和FA影响的孩子，总共1,500名受试者)中对AIM 1中所有有希望的SNPs进行基因分型。我们将进行联合分析，将1000个三者结合在一起，总共3000个对象。我们将在第二阶段使用全基因组意义截止值(p&lt；10-7)。这项研究将是美国第一个大规模的FA GWA研究。鉴于我们对FA的病因了解有限，且缺乏高度有利的FA候选基因，GWA研究为剖析FA的遗传学基础提供了最好的可用方法。这项研究具有以下优势：(1)利用现有研究样本进行高成本效益的研究；(2)大样本规模，确保有足够的统计能力来实现主要目标；(3)使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。我们期待这项研究将有助于鉴定新的FA基因座，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、精细的定位、测序和功能研究，以进一步阐明哪些特定的变异是原因，其生物学机制是什么，以及它们如何与其他遗传或环境因素相互作用。这项拟议研究的一个特别优点是，鉴于良好的基础设施和资源，它为未来的FA研究提供了巨大的潜力。总体而言，这项研究和未来的研究将有助于开发一个有希望的范例，以识别FA的高危个体，并制定有效的FA预防和治疗策略。

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.