GENETICS OF ASTHMA AND BRONCHIAL HYPERRESPONSIVENESS

哮喘的发展需要接触激动剂，如 过敏原和环境污染物，以及宿主或 遗传因素。对支气管炎遗传学的认识 高反应性(BHR)和过敏将描述以下机制 对哮喘的发病机制和治疗具有重要意义。虽然这两种基因 环境因素及其相互作用被认为是重要的， 他们的确切作用还没有完全被理解。这是一个独特的机会 通过重新仔细检查一项研究哮喘的遗传学 哮喘患者的特征人群，并通过研究他们的 家人。这些先驱来自哈伦的“哮喘”中心Betrixoord， 荷兰成立于1962年。与我们的荷兰人合作 合作调查员Dirkje Postma博士的数据可在大约 1200名患者在1963-1970年首次使用相同的方案进行研究。 对这些原始人的子孙进行的家庭研究 先知仪式正在进行中。目前，已有85个完整的家庭 特征性和临床数据和DNA可用于分析 巴尔的摩。目前正在确定家属，以便我们能够进行测试 通过分离分析对遗传模型进行拟合。的主要目标是 这一建议是为了确定导致支气管高反应性的主要基因 (BHR)和哮喘通过与高度多态的DNA标记连锁而发生。自.以来 过敏通常与哮喘有关，这是该提案的第二个目标 是使用类似的连锁研究来确定特应性过敏的主要基因。 过敏因素包括皮试对常见过敏原的反应性、血清 将研究总IgE水平和特异性IgE水平以及血液中的嗜酸性粒细胞。 将对哮喘、BHR分别进行复杂分离分析 还有过敏症。分离分析中的最简约模型 将用于连锁分析。最初， 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测试。当链接是 检测到后，将对该特定区域的候选基因进行研究。

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.