Post Genome-Wide Association Study of Food Allergy

描述（由申请人提供）：食物过敏（FA）是美国和世界范围内日益严重的临床和公共卫生问题。预防和治疗FA的主要障碍是我们对其病因和生物学机制的不完全了解。FA被认为是一种复杂的性状，由多种环境和遗传因素决定。阳性家族史是公认的过敏性疾病的预测因子。我们发表的和初步的数据强调了遗传因素在FA中的重要作用。该建议是我们正在进行的FA全基因组关联研究（GWAS）的自然延伸，该研究包括来自芝加哥的1,000名高加索FA病例-父母三人组。使用lllumina HumanOmni1-Quad BeadChip进行基因分型。GWAS的初步结果令人鼓舞。本提案将通过在芝加哥和波士顿注册的两个大型、表型良好的研究队列来实现以下目标，这两个队列是为使用标准数据收集方案进行FA的大规模分子遗传流行病学研究而设计的。目的1。独立高加索样本的确证研究：我们计划对从GWAS中鉴定出的有希望的snp /拷贝数变异（CNVs）进行基因分型，并使用病例对照设计对1200名高加索儿童的独立样本进行联合分析：600名高加索FA病例和600名来自芝加哥的匹配非过敏对照。目的IB.多种族样本中的复制研究：对于那些在1A的联合分析中达到全基因组显著性（p<10-7）的snp /CNVs，我们计划使用巢式病例对照设计在独立样本（n= 1800）中进一步进行基因分型和测试遗传相关性：从波士顿队列中确定600例FA病例和1200例匹配的非过敏对照。其中三分之二是非洲裔美国人，三分之一是高加索人/西班牙人。目标2。基于Aim 1A和1B的发现，我们将继续在有希望的地区发现新的snp / cnv，通过对组合样本（n=6000名受试者）进行集中的基因分型和关联测试，包括来自芝加哥的1000个FA三组和600个FA病例对照对（n=4200）和来自波士顿的600个FA病例和1200个对照（n=1800）。本研究将是美国多种族人群中首次大规模的FA后GWAS。考虑到强大的初步数据、独特的资源和团队的跟踪记录，它有很高的成功可能性。这项研究的发现可能会改变我们对FA原因的理解，并为未来的研究提供信息。

DESCRIPTION (provided by applicant): Food allergy (FA) is a growing clinical and public health problem in the U.S. and worldwide. The major obstacle in preventing and treating FA has been our incomplete understanding of its etiology and biological mechanisms. FA is believed to be a complex trait and determined by multiple environmental and genetic factors. A positive family history is a well-recognized predictor of allergic diseases. Our published and preliminary data underscore the important roles of genetic factors in FA. This proposal is a natural extension of our ongoing genome-wide association study (GWAS) of FA, which includes 1,000 Caucasian FA case-parents trios from Chicago. Genotyping was performed using the lllumina HumanOmni1-Quad BeadChip. Preliminary results from the GWAS are encouraging. This proposal will accomplish the following aims by utilizing two large, well-phenotyped study cohorts enrolled in Chicago and Boston, which were designed for large-scale molecular genetic epidemiologic studies of FA using a standard data collection protocol. Aim 1A. Confirmation study in an independent Caucasian sample: We plan to genotype promising SNPs/copy number variations (CNVs) identified from the GWAS and perform joint analysis in an independent sample of 1,200 Caucasian children using a case-control design: 600 Caucasian FA cases and 600 matched non-allergic controls from Chicago. Aim IB. Replication Study in a Multiethnic Sample: For those SNPs/CNVs that have reached genome-wide significance (p<10-7) in the joint analysis from 1A, we plan to further genotype and test genetic association in an independent sample (n=1,800) using a nested case-control design: 600 FA cases and 1,200 matched non-allergic controls identified from the Boston Cohort. Of those, two thirds are African Americans and one third are Caucasians/Hispanics. Aim 2. Fine Mapping to Search for Causative Variants: Based on the findings in Aim 1A and 1B, we will proceed to the discovery of novel SNPs/CNVs in the promising regions, by focused genotyping and association testing in the combined samples (n=6000 subjects), including the 1,000 FA trios and 600 FA case-control pairs from Chicago (n=4200) and 600 FA cases and 1200 controls from Boston (n=1800). This proposed study will be the first large-scale Post GWAS of FA in multi-ethnic U.S. populations. It has a high likelihood of success given the strong preliminary data, unique resources, and the team's track records. Findings from this study may transform our understanding of the causes of FA and inform future studies. PUBLIC HEALTH RELEVANCE (Provided by applicant): Food allergy (FA) is a growing clinical and public health problem in the US and worldwide. The central focus of this proposal is to further replicate promising genetic variants identified by the ongoing genome-wide association study (GWAS) of FA and to search for causative genes of FA. This will be the first large-scale post GWAS of FA in multi-ethnic US populations. Findings from this study may help understand the causes of FA and eventually help develop effective strategies for prevention and treatment of FA.