GENETICS OF ASTHMA AND BRONCHIAL HYPERRESPONSIVENESS

阐明遗传因素在常见复杂疾病的发生和表达中的作用，并了解基因与环境的相互作用具有重大的公共卫生意义。这些遗传方法将进一步深入了解这些疾病的病理生理学，提供更有效的治疗干预措施，提供新的症状前诊断方法，从而制定出对易感人群进行早期疾病预防的战略，并描绘出基因与特定治疗反应之间的相互作用(药物遗传学)。这是RO1的续订申请，该项目最初资助了5年，是首批绘制哮喘易感基因图谱的项目之一，该项目旨在招募哮喘家庭并进行全基因组筛查，以检测具有连锁证据的染色体区域。这项提议是与格罗宁根大学的Dirkje Postma教授合作的项目。在荷兰哮喘基金的资助下，在格罗宁根对这些家庭进行了确定和临床特征分析。对家系数据进行临床和遗传分析以及对家系进行完整的基因组筛查是原始RO1的目标。这些目标已经实现，并在几个领域取得了更多进展。一种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)临床确定哮喘和几个相关表型的家系，2)分离分析与参数和非参数连锁分析，以及3)分子遗传学区域，其中候选基因连锁和关联方法以及基因组筛查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之所以成为可能，是因为格罗宁根有一个独特的机会，可以研究通过哮喘先证者确定的荷兰家庭的基因同质性群体，这些人最初是在25到35年前进行研究的，后来又与他们的配偶、子女和孙辈一起进行了重新研究。因此，我们有一个适当确定用于隔离分析的家庭样本，非常适合于连锁分析和精细作图，以及一个来自荷兰受限人群的病例对照样本，用于关联研究(先证者与未受影响的配偶)。对最初140个家族的基因组筛查结果显示，有几个感兴趣的区域是新的，还有几个复制了其他报道的研究结果。在最初的荷兰哮喘基金赠款下，收集了92个家庭的数据，用于我们最初的分析。根据目前的荷兰赠款，正在确定另外108个家庭的特征，总共有200个家庭已被确定为相同的方案。这种同质的荷兰人群非常适合使用本次更新中提出的多方面方法来精细定位哮喘的易感基因和相关的表型。

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.