Post Genome-Wide Association Study of Food Allergy

描述（由申请人提供）：食物过敏（FA）是美国和全球日益严重的临床和公共卫生问题。目前防治FA的主要障碍是对其病因学和生物学机制的认识不足。FA被认为是一个复杂的性状，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素。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。这项提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名白人FA病例父母三人组。使用Illumina HumanOmni 1-Quad BeadChip进行基因分型。GWAS的初步结果令人鼓舞。本提案将通过利用在芝加哥和波士顿招募的两个大型、表型良好的研究队列来实现以下目标，这两个队列旨在使用标准数据收集方案进行大规模FA分子遗传流行病学研究。目标1A。在一个独立的白人样本中的确认研究：我们计划对从GWAS中鉴定的有希望的SNP/拷贝数变异（CNV）进行基因分型，并使用病例对照设计在1,200名白人儿童的独立样本中进行联合分析：600名白人FA病例和600名来自芝加哥的匹配的非过敏对照。目标1B。在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/CNV，我们计划使用巢式病例对照设计在一个独立样本（n= 1，800）中进一步进行基因分型和遗传相关性测试：600例FA病例和1，200例匹配的非过敏对照，从波士顿队列中确定。其中三分之二是非洲裔美国人，三分之一是高加索人/西班牙裔。目标2.精细映射以搜索因果变体：基于目标1A和1B中的发现，我们将继续在有希望的区域中发现新的SNPs/CNVs，通过集中的基因分型和组合样本中的关联测试（n=6000名受试者），包括来自芝加哥的1,000名FA三人组和600名FA病例-对照组（n=4200）以及来自波士顿的600名FA病例和1200名对照组（n=1800）。这项拟议的研究将是美国多种族人群中首次大规模的FA后GWAS。鉴于强大的初步数据、独特的资源和团队的跟踪记录，它成功的可能性很高。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.