GENETICS OF ASTHMA AND BRONCHIAL HYPERRESPONSIVENESS

哮喘的发展需要暴露于激发剂，如 过敏原和环境污染物，以及宿主或 遗传因素了解支气管炎的遗传学 高反应性（BHR）和变态反应将描述机制， 在哮喘的发病机制和治疗中具有重要意义。 虽然两者的基因 环境因素及其相互作用被认为是重要的， 它们的确切作用尚未完全了解。一个独特的机会存在， 通过重新仔细检查一个 哮喘患者的特征人群，并通过研究他们的 家庭先证者来自哈伦的“哮喘”中心Beatrixoord， 荷兰，始于1962年。与荷兰合作 共同研究者Dirkje Postma博士提供的数据约为 1963-1970年首次使用相同方案研究的1200例患者。 对这些原始的子孙的家庭研究 先证者正在进行中。目前，已有85个完整的家庭 特征和临床数据和DNA可用于分析， 巴尔的摩。家庭正在确定，以便我们能够测试 通过分离分析来拟合遗传模型。 的主要目的 本研究旨在寻找与支气管高反应性相关的主要基因 (BHR)与哮喘的关系。以来 过敏症通常与哮喘有关，这是该提案的第二个目标 是用类似的连锁研究来确定特应性的主要基因。 过敏因素，包括皮肤试验对常见过敏原的反应性，血清 将研究总IgE和特异性IgE水平以及血液嗜酸性粒细胞增多症。 将对哮喘、BHR单独进行复杂分离分析 和过敏。分离分析中最简约的模型 将用于连锁分析。最初，候选区域的 将对基因组进行评估。然后，对基因组进行系统的搜索， 使用高度多态的信息标记进行。当一个链接 如果检测到，将研究该特定区域的候选基因。

The development of asthma requires exposure to inciting agents such as allergens and environmental pollutants, as well as the presence of host or genetic factors. Understanding the genetics of bronchial hyperresponsiveness (BHR) and allergy will delineate mechanisms that are important in the pathogenesis and therapy of asthma. While both genetic and environmental factors and their interactions are felt to be important, their precise role is not fully understood. A unique opportunity exists to investigate the genetics of asthma by reexamining a carefully characterized population of patients with asthma, and by studying their families. The probands are from the "asthma" center Beatrixoord in Haren, The Netherlands which was started in 1962. In collaboration with our Dutch co-investigator, Dr Dirkje Postma, data are available on approximately 1200 patients who were first studied in 1963-1970 using the same protocol. Family studies of the children and grandchildren of these original probands are underway. At this time, 85 complete families have been characterized and clinical data and DNA are available for analysis in Baltimore. Families are being ascertained so that we will be able to test the fit of genetic models through segregation analyses. The major aim of this proposal is identify major genes for bronchial hyperresponsiveness (BHR) and asthma by linkage with highly polymorphic DNA markers. Since allergy is commonly associated with asthma, a second goal of this proposal is to identify major genes for atopy using similar linkage studies. Allergic factors including skin test reactivity to common allergens, serum total and specific IgE levels, and blood eosinophilia will be studied. Complex segregation analysis will be performed separately for asthma, BHR and allergy. The most parsimonious model from the segregation analysis will be used for linkage analysis. Initially, candidate regions of the genome will be evaluated. Then, a systematic search of the genome will be performed using highly polymorphic informative makers. When a linkage is detected, candidate genes in that specific area will be studied.