Post Genome-Wide Association Study of Food Allergy

描述(由申请人提供)：食物过敏(FA)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。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了解不够深入。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子。我们已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1000名高加索人FA病例-父母三人。基因分型使用llLumina Human Omni1-Quad BeadChip进行。全球气候变化研究的初步结果令人鼓舞。这项建议将通过利用在芝加哥和波士顿登记的两个大型、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大规模FA分子遗传流行病学研究而设计的。目标1 A。在一个独立的高加索样本中进行的验证性研究：我们计划对从GWAS中发现的有希望的SNPs/拷贝数变异(CNV)进行分型，并使用病例对照设计在1200名高加索儿童的独立样本中进行联合分析：600名高加索FA病例和600名来自芝加哥的匹配的非过敏对照。瞄准IB。多种族样本中的重复研究：对于从1A开始的联合分析中达到全基因组意义的SNPs/CNV(p&lt；10-7)，我们计划使用嵌套病例对照设计在一个独立样本(n=1,800)中进一步分型和测试遗传关联：从波士顿队列中确定600例FA病例和1,200例匹配的非过敏对照。在这些人中，三分之二是非裔美国人，三分之一是高加索人/西班牙人。目的2.精细定位以寻找致病变异：基于目标1A和1B的发现，我们将继续在有希望的区域发现新的SNPs/CNV，通过集中基因分型和关联测试在组合样本(n=6000)中进行，包括来自芝加哥的1,000个FA三联体和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)。这项拟议的研究将是第一次在美国多种族人群中进行大规模的后GWAFA研究。考虑到强大的初步数据、独特的资源和团队的记录，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病因的理解，并为未来的研究提供参考。

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.