Parent-of-Origin Effects on Food Allergy

来源亲本对食物过敏的影响

• 批准号: 8488814
• 负责人: Xin Liu
• 金额: $ 7.35万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-10 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8488814
• 关键词: Accident and Emergency department; Address; Adult; Affect; Alleles; Allergic Disease; Anaphylaxis; Case-Control Studies; Caucasians; Caucasoid Race; Chicago; Child; Clinical; Complement; Complex; Data; Development; Egg White; Environment; Environmental Risk Factor; Family; Fathers; Food; Food Hypersensitivity; Gender; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genome; Genotype; Heritability; Heterogeneity; Hypersensitivity; IgE; Individual; Inherited; Lead; Mediating; Milk Hypersensitivity; Mothers; Onset of illness; Parents; Pathway Analysis; Peanuts - dietary; Play; Predisposition; Prevention strategy; Public Health; Publications; Reaction; Recording of previous events; Relative Risks; Research Design; Risk; Role; Sample Size; Sampling; Severities; Single Nucleotide Polymorphism; Subgroup; Testing; Variant; Visit; base; cohort; cost; design; early childhood; genetic variant; genome wide association study; high risk; imprint; maternal imprint; novel; offspring; public health relevance; success; trait

DESCRIPTION (provided by applicant): Food allergy (FA), a hypersensitivity reaction to food, is a growing clinical and public health problem in the U.S. and worldwide. FA is a complex trait, as a result of multiple genetic and environmental factors and their interactions. However, specific genetic markers that can modulate individual susceptibility to FA remain to be determined. Our ongoing genome-wide association study (GWAS) of FA in the Chicago Cohort is the first study to comprehensively identify susceptibility variants for FA. Similar to other GWAS, it treats the genetic effects from the paternally- and maternally-transmitted allele on FA equally, such that FA-associated imprinted genes could not be identified. Moreover, no study has examined maternally-mediated genetic effects on FA. As an early childhood onset disease, maternal genotypes may play crucial roles in the development of FA, possibly through their influence on the intrauterine environment. To complement our GWAS of FA and search for the missing heritability, the central focus of this study is to examine maternal and imprinting effects on FA, two types of parent-of-origin effects (POE), by leveraging the existing GWAS data generated in 851 FA families from the Chicago Cohort. Specifically, we propose to accomplish two primary aims. Aim1: we will test maternally-mediated genetic effects on FA in 631 Caucasian families (~80% of the samples from the GWAS of FA) using log-linear likelihood ratio tests (LL-LRT), which are able to examine genetic effects through the offspring, mother, and both. We also will conduct pathway analysis of maternal genetic effects on FA. Aim2: We will test for imprinting effects, which represent the relative risk of FA cases inheriting a maternally- transmitted allele vs. the risk of FA cases inheriting a paternally-transmitted allele, in 631 Caucasian FA families using LL-LRT after the adjustment of confounding effects from maternal genotypes. This study will be the first large-scale genome-wide study of POE on FA. This represents a significant step forward in complementing our understanding of the genetic basis of FA. The findings could partially explain the missing heritability of the genome regarding the genetic susceptibility of FA. We anticipate that this study may transform our understanding of FA and lead to the identification of novel genetic mechanisms of FA, which will help us to develop a promising paradigm for identifying individuals at high risk for FA, and ultimately design effective strategies for the prevention and treatment of FA.

描述（由申请人提供）：食物过敏 (FA) 是一种对食物的过敏反应，是美国和全世界日益严重的临床和公共卫生问题。 FA 是一种复杂的性状，是多种遗传和环境因素及其相互作用的结果。然而，能够调节个体对 FA 易感性的特定遗传标记仍有待确定。我们正在进行的芝加哥队列中 FA 的全基因组关联研究 (GWAS) 是第一项全面识别 FA 易感性变异的研究。与其他 GWAS 类似，它同等对待父系和母系传播的等位基因对 FA 的遗传影响，因此无法识别 FA 相关的印记基因。此外，尚无研究探讨母体介导的遗传对 FA 的影响。作为一种儿童早期发病的疾病，母体基因型可能通过影响宫内环境而在 FA 的发展中发挥至关重要的作用。为了补充我们的 FA GWAS 并寻找缺失的遗传力，本研究的重点是检查母体和印记效应 通过利用芝加哥队列 851 个 FA 家族中生成的现有 GWAS 数据，对 FA 进行了两种类型的亲本效应 (POE) 的研究。具体来说，我们建议实现两个主要目标。目标 1：我们将使用对数线性似然比检验 (LL-LRT) 测试 631 个白人家庭（约 80% 的 FA GWAS 样本）中母体介导的 FA 遗传效应，该检验能够通过以下方式检查遗传效应：后代、母亲，以及两者。我们还将对 FA 的母体遗传影响进行通路分析。目标 2：我们将测试印记效应，它代表 FA 病例遗传母系遗传基因的相对风险 调整母体基因型的混杂效应后，在 631 个使用 LL-LRT 的白人 FA 家庭中，比较了遗传性等位基因与遗传父系遗传等位基因的 FA 病例的风险。这项研究将是第一个针对 FA 的 POE 大规模全基因组研究。这代表着在补充我们对 FA 遗传基础的理解方面向前迈出了重要一步。这些发现可以部分解释关于 FA 遗传易感性的基因组遗传性缺失。我们预计这项研究可能会改变我们对 FA 的理解，并导致对 FA 的新遗传机制的识别，这将有助于我们开发一个有前景的范式来识别 FA 高风险个体，并最终设计有效的预防和预防策略。 FA的治疗。