GENETICS OF ASTHMA AND BRONCHIAL HYPERRESPONSIVENESS

描述遗传因素在常见复杂疾病的发展和表达中的作用，并了解基因-环境相互作用具有重大的公共卫生意义。这些遗传学方法将提供进一步深入了解这些疾病的病理生理学，更有效的治疗干预措施，新的诊断方法，症状前诊断，将导致易感个体的早期疾病预防战略的发展和基因型和特定治疗反应之间的相互作用的划定（药物遗传学）。 这是一个RO 1的更新申请，最初资助了5年，是第一个绘制哮喘易感基因的项目之一，旨在招募哮喘家族并进行全基因组筛查，以检测具有连锁证据的染色体区域。 该建议是与格罗宁根大学Dirkje Postma教授的合作项目。 在荷兰哮喘基金的资助下，在格罗宁根对这些家族进行了确认和临床表征。 原始RO 1的目标是对家族数据进行临床和遗传分析以及对家族进行完整的基因组筛选。 这些目标已经实现，并在若干领域取得了新的进展。 描述哮喘和相关表型的遗传基础的多方面方法正被用于1）哮喘和几种相关表型都被充分表征的家庭的临床确定，2）分离分析与参数和非参数连锁分析一起进行沿着的分析方法，3）分子遗传学领域，其中候选基因方法用于连锁和关联以及基因组筛选的结果被用于定位哮喘易感基因。 这种研究哮喘遗传学的方法是可能的，因为在格罗宁根有独特的机会研究遗传同质的荷兰家庭人口，这些家庭是通过25至35年前最初研究的哮喘先证者确定的，沿着与他们的配偶、子女和孙辈一起重新研究的。 因此，我们有一个样本的家庭适当确定的分离分析，理想的连锁分析和精细映射，以及一个病例对照样本的关联研究（先证者与未受影响的配偶）从一个有限的荷兰人口。 前140个家族的基因组筛选结果显示了几个新的感兴趣的区域，还有几个重复了其他报告研究的结果。 根据最初的荷兰哮喘基金会赠款，收集了92个家庭的数据，用于我们的原始分析。 根据目前荷兰的赠款，正在对另外108个家庭进行鉴定，总共有200个家庭已通过同一议定书得到确认。这种同质的荷兰人口是理想的精细地图易感基因的哮喘和相关的表型使用多方面的方法提出了在这个更新。

Delineating the role of genetic factors in the development and expression of common complex disorders, and understanding gene- environment interactions has major public health significance. These genetic approaches will provide further insight into the pathophysiology of these diseases, more effective therapeutic interventions, new diagnostic methods for pre-symptomatic diagnosis that would lead to the development of strategies for early disease prevention in susceptible individuals and delineation of the interaction between genotype and response to specific treatments (pharmacogenetics). This is a renewal application for a RO1 that was originally funded for 5 years and was one of the first projects on mapping susceptibility genes for asthma that was designed to recruit asthma families and perform a genome wide screen to detect chromosomal regions with evidence for linkage. This proposal is a collaborative project with Professor Dirkje Postma at the University o f Groningen. The ascertainment and clinical characterization of the families has been performed in Groningen with funding from the Dutch Asthma Funds. The clinical and genetic analysis of the family data as well as performing a complete genome screen on the families were the goals of the original RO1. These aims have been met and additional progress has been made in several areas. A multifaceted approach to delineate the genetic basis of asthma and associated phenotypes is being utilized in 1) the clinical ascertainment of families where both asthma and several related phenotypes are fully characterized, 2) the analytical methods where both segregation analysis is performed along with both parametric and nonparametric linkage analysis, and 3) the molecular genetic areas where a candidate gene approach for both linkage and association as well as the results of a genome screen are being utilized for mapping asthma susceptibility genes. This approach to investigate the genetics of asthma has been possible because of the unique opportunity in Groningen to study a genetically homogenous population of Dutch families identified through probands with asthma who were originally studied 25 to 35 years ago and who have been restudied along with their spouses, children and grandchildren. Therefore, we have a sample of families appropriately ascertained for segregation analysis, ideal for linkage analysis and fine mapping as well as a case-control sample for association studies (probands versus unaffected spouses) from a restricted Dutch population. The results of a genome screen in the first 140 families show several regions of interest that are novel and several that replicate the results in other reported studies. Under the original Dutch Asthma Fund grant, data was collected on 92 families which were used for our original analyses. Under the current Dutch grant, an additional 108 families are being characterized for a total of 200 families that have been ascertained with the same protocol. This homogenous Dutch population is ideal to fine map susceptibility genes for asthma and associated phenotypes using the multifaceted approach proposed in this renewal.