Genetics of Asthma and Bronchial Hyperresponsiveness

描述（由申请人提供）：哮喘是一种炎症性气道疾病，由哮喘易感基因和特应性与多种环境暴露之间的相互作用引起。似乎没有单一的易感基因会带来主要的风险，但更有可能的是，在暴露于特定环境因素后，一系列具有相互作用的基因会增加哮喘和/或其他特应性疾病的风险。我们收集了200个荷兰哮喘家庭的特征，最近扩大到包括额外的437例支气管高反应性（BHR）的三人组，其中366例患有临床哮喘。这两个荷兰家庭的样本构成了这种竞争性复兴的基础。我们已经与荷兰格罗宁根大学的Dirkje S Postma教授及其同事合作了十多年。我们对来自荷兰北部的同质荷兰人口的研究非常有成效，该研究是通过大约25年前患有哮喘的父母确定的。我们假设哮喘和特应性的重要易感基因位于染色体2q和5q上，我们有强有力的证据表明两者之间存在联系。为了研究这一点，我们将继续对这两条染色体进行定位克隆，并结合我们的荷兰家族和三人组进行定位候选基因关联研究，并评估基因与环境的相互作用（暴露于被动吸烟）。本提案的具体目的是：1)完成新437组三胞胎的表型数据集，并对其临床特征进行分析，与家族人群进行比较；2)鉴定两种表型的2q染色体上与哮喘相关的基因；3)利用定位克隆和定位候选基因联合方法在荷兰三重奏和家族中鉴定5q31-33染色体上哮喘和BNR的易感基因；4)利用200个先证者的纵向数据评估哮喘易感基因，以确定荷兰人群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对候选基因进行优先排序，获得基因组结构并研究我们人群中的序列变异，以促进鉴定在哮喘和相关表型发展中重要的基因。

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.