Sex-specific genetic architecture of asthma risk in children

描述(申请人提供)：在2000万患有哮喘的美国人中，超过30%的人年龄在18岁或以下，使哮喘成为影响美国儿童的最常见的慢性病。儿童哮喘的患病率在男性和女性之间差异很大，这表明这种复杂疾病背后有性别特有的遗传结构。这项建议的总体目标是在一项对哮喘风险较高的幼儿进行的出生队列研究中，确定导致哮喘易感性性别差异的基因和途径。 本研究方案包含三个主要目的。在目标1中，通过DMA微阵列测量的全基因组表达模式将被用来识别在鼻病毒刺激的单个核细胞中差异表达的基因，这些基因来自干扰素-伽马反应水平高的儿童(即高反应儿童)与干扰素-伽马反应水平低的儿童(即低反应儿童)。为了专注于表现出性别差异的基因，这些实验将分别在男孩和女孩身上进行。在目标2中，将评估基因中的SNPs对干扰素-伽马反应和其他5种与哮喘相关的表型的贡献，这些基因在一组310名年幼儿童中，显示了一种性别差异的高反应者和低反应者之间的表达差异，而不是两种性别。在目标3中，将使用适当的实验方法对位于差异表达基因并与哮喘相关的表型变异相关的SNPs进行功能表征，例如，荧光素酶报告分析启动子区域和microRNA结合位点SNPs，等位基因特异性定量编码SNPs，以及5‘和3’非翻译区SNPs的mRNA稳定性分析。这三个目标的结果将为性别特定的基因调控机制提供新的见解，这些机制可能有助于在青少年男孩和女孩中观察到哮喘患病率的显着差异。这项研究将通过提供关于哮喘在青春期前在男孩中更常见，然后在青春期后在女孩中更常见的新信息来影响公共健康。了解这种性别差异的原因将导致治疗和预防儿童和成人哮喘的新的更好的方法。

DESCRIPTION (provided by applicant): Of the 20 million Americans suffering from asthma, more than 30% of them are 18 years old or younger, making asthma the most common chronic illness affecting children in the United States. The prevalence of childhood asthma differs greatly between males and females, suggesting that there is a sex specific genetic architecture underlying this complex disease. The overall objective of this proposal is to identify genes and pathways that contribute to sex-specific differences in asthma susceptibility in a birth cohort study of young children who are at an elevated risk for asthma. This research proposal contains three main aims. In Aim 1, genome-wide expression patterns, measured by DMA microarrays, will be used to identify genes that are differentially expressed in rhinovirus stimulated mononuclear cells from children with high levels of interferon-gamma response (i.e. high response children) compared to children with low levels of interferon-gamma response (i.e. low response children). To focus on genes that show sex-specific differences in expression, these experiments will be conducted separately in boys and girls. In Aim 2, SNPs in genes that show differences in expression between high and low responders in one sex, but not both, will be evaluated for their contribution to sexspecific variation in interferon-gamma response and five other asthma-related phenotypes in a cohort of 310 young children. In Aim 3, the SNPs that are both located in differentially expressed genes and associated with asthma-related phenotypic variation will be functionally characterized using an appropriate experimental method, e.g. luciferase reporter assays for promoter region and microRNA binding site SNPs, allele-specific quantification for coding SNPs, and mRNA stability assays for SNPs in 5' and 3' untranslated regions. The results from these three Aims will provide novel insight into the sex-specific mechanisms for gene regulation that may contribute to the striking differences observed in asthma prevalence in adolescent boys and girls. This research will impact public health by providing new information about what causes asthma to be more common in boys before puberty and then more common in girls after puberty. Understanding the cause of this difference between the sexes will lead to new and better ways to treat and prevent asthma in both children and adults.