Genetics of Asthma and Bronchial Hyperresponsiveness

描述(由申请人提供)：哮喘是一种炎症性呼吸道疾病，由哮喘和特应性疾病的易感基因与不同的环境暴露组之间的相互作用引起。似乎没有单一的易感基因会带来重大风险，但更有可能是一系列具有交互作用的基因，这些基因会在暴露于特定环境因素后增加哮喘和/或其他特应性疾病的风险。我们收集了具有良好特征的200个家庭的荷兰哮喘人群，最近扩大到包括另外437个患有支气管高反应性(BHR)的三联体，其中366人患有临床哮喘。这两个荷兰家庭的样本构成了这种竞争性更新的基础。十多年来，我们一直与荷兰格罗宁根大学的Dirkje S博士教授和她的同事们合作。我们对来自荷兰北部的这一同质荷兰人的研究非常有成效，这是通过一位患有哮喘的父母确定的，该父母最初在大约25年前表现出哮喘的特征。我们假设哮喘和特应性疾病的重要易感基因定位于染色体2q和5q，在这两个染色体上我们有强有力的证据表明存在连锁。为了研究这一点，我们将继续对这两条染色体进行位置克隆方法，同时使用我们的荷兰家庭和TRIO进行位置候选基因关联研究，并评估基因与环境的相互作用(暴露在被动吸烟中)。该建议的具体目的是：1)完成新的437个三联体的表型数据集，并对它们的临床特征进行分析，以便与家族人群进行比较；2)在荷兰三联体和家族中，使用位置克隆和位置候选基因方法相结合的方法，识别染色体2q上与哮喘相关的两种表型：FEV1/VC和血清总IgE水平；3)使用位置克隆和位置候选基因方法相结合的方法，识别染色体5q31-33上的哮喘易感基因和BNR，4)使用200名先证者的纵向数据，评估哮喘易感基因，以确定在我们荷兰人群中的意义及其在哮喘严重程度(哮喘进展)中的潜在作用。这些科学方法将使我们能够根据现有的图谱位置和生物学相关性知识确定候选基因的优先顺序，获得基因组结构并研究我们人群中的序列变异，以便于识别在哮喘及其相关表型的发展中至关重要的基因。

DESCRIPTION (provided by applicant): Asthma is an inflammatory airways disease caused by an interaction between susceptibility genes for asthma and atopy and a diverse group of environmental exposures. It appears that there is no single susceptibility gene that confers major risk, but more likely a series of genes with interactive effects that increase the risk for asthma and/or other atopic conditions after exposure to specific environmental factors. We have collected a well-characterized Dutch asthma population of 200 families, which has been recently expanded to include an additional 437 trios with bronchial hyperresponsiveness (BHR), 366 of whom have clinical asthma. These two samples of Dutch families form the basis for this competitive renewal. We have been collaborating with Professor Dirkje S Postma MD, PhD and her colleagues at the University of Groningen, the Netherlands for over 10 ten years. Our studies on this homogeneous Dutch population from northern Holland ascertained through a parent with asthma who was originally characterized approximately 25 years previously have been very productive. We hypothesize that important susceptibility genes for asthma and atopy map to chromosomes 2q and 5q where we have strong evidence for linkage. To investigate this, we will continue positional cloning approaches for these two chromosomes in conjunction with positional candidate gene association studies using both our Dutch families and trios, with the evaluation of gene-environment interactions (exposure to passive smoking). The specific aims of this proposal are: 1) Complete the phenotypic data set on the new 437 trios and perform analyses of their clinical characteristics for comparison with the family population 2) Identify genes on chromosome 2q related to asthma for two phenotypes: FEV1/VC and total serum IgE levels using a combination of positional cloning and positional candidate gene approaches in the Dutch trios and families, 3) Identify susceptibility genes for asthma and BNR on chromosome 5q31-33 using a combination of positional cloning and positional candidate gene approaches in the Dutch trios and families, 4) Evaluate asthma susceptibility genes to determine significance in our Dutch populations and their potential role in asthma severity (progression of asthma) using the longitudinal data on the 200 probands. These scientific approaches will allow us to prioritize candidate genes based on available knowledge of map position and biological relevance, obtain genomic structure and study sequence variants in our populations to facilitate the identification of genes that are important in the development of asthma and associated phenotypes.