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）是对食物的过敏反应，是美国和全球范围内日益增长的临床和公共卫生问题。由于多种遗传和环境因素及其相互作用，FA是一个复杂的特征。但是，可以调节个人对FA敏感性的特定遗传标记仍有待确定。我们正在进行的全基因组协会研究（GWAS）在芝加哥队列中是首次全面识别FA的易感性变体的研究。与其他GWAS相似，它可以同样地对待FA的遗传作用，因此无法鉴定出与FA相关的印迹基因。此外，尚无研究检查对FA的母体介导的遗传作用。作为幼儿发作的疾病，母体基因型可能在FA的发展中起着至关重要的作用，这可能是由于它们对宫内环境的影响。为了补充我们的FA的GWA并寻找缺失的遗传力，这项研究的主要重点是检查孕产妇和烙印效果 在FA上，通过利用来自芝加哥队列的851 FA家族产生的现有GWAS数据的两种类型的父母效应（POE）。具体来说，我们建议实现两个主要目标。 AIM1：我们将使用对数线性的可能性比测试（LL-LRT）测试631个高加索家族（约80％的来自FA的样本）对FA的遗传作用（〜80％），这些测试能够通过后代，母亲，母亲以及两者都能检查遗传效应。我们还将对母体遗传作用对FA进行途径分析。 AIM2：我们将测试烙印效应，这代表了FA案件的相对风险 在调整了母体基因型的混杂作用后，在631个高加索FA家族中，在631个高加索FA家族中传输了等位基因与FA病例的风险。这项研究将是对FA的POE的首次大规模基因组研究。这代表了我们对我们对FA遗传基础的理解的重要一步。这些发现可能部分解释了基因组关于FA遗传敏感性的缺失遗传力。我们预计这项研究可能会改变我们对FA的理解，并导致FA的新遗传机制的鉴定，这将有助于我们开发有希望的范式，以识别具有FA高风险的个体，并最终为预防和治疗FA设计有效的策略。