GENETICS OF ASTHMA AND BRONCHIAL HYPERRESPONSIVENESS

哮喘和支气管高反应性的遗传学

• 批准号: 2911080
• 负责人: Deborah A. Meyers
• 金额: $ 40.26万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-10 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2911080
• 关键词: Europe; asthma; blood chemistry; clinical research; family genetics; gene environment interaction; genetic mapping; genetic markers; genetic polymorphism; genetic susceptibility; human data; human genetic material tag; human subject; human tissue; linkage mapping; longitudinal human study; serology /serodiagnosis

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.

描述遗传因素在常见复杂疾病的发展和表达中的作用，并了解基因与环境的相互作用具有重大的公共卫生意义。这些遗传学方法将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、用于症状前诊断的新诊断方法，从而制定易感个体的早期疾病预防策略，并描述基因型与对特定治疗（药物遗传学）的反应之间的相互作用。 这是 RO1 的更新申请，该 RO1 最初资助了 5 年，是首批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选，以检测具有连锁证据的染色体区域。 该提案是与格罗宁根大学 Dirkje Postma 教授的合作项目。 在荷兰哮喘基金会的资助下，在格罗宁根对这些家庭进行了查明和临床特征分析。 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是最初 RO1 的目标。 这些目标已经实现，并且在几个领域取得了更多进展。 描述哮喘和相关表型遗传基础的多方面方法正在用于：1）对哮喘和几种相关表型进行充分表征的家庭的临床确定，2）分析方法，其中分离分析与参数和非参数连锁分析一起进行，3）分子遗传领域，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绘制哮喘易感基因图谱。 这种研究哮喘遗传学的方法之所以成为可能，是因为格罗宁根有独特的机会来研究荷兰家庭的遗传同质群体，这些家庭是通过哮喘先证者确定的，这些先证者最初是在 25 至 35 年前进行研究的，后来与他们的配偶、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的家庭样本用于隔离分析，非常适合连锁分析和精细绘图，以及来自有限荷兰人口的用于关联研究（先证者与未受影响的配偶）的病例对照样本。 前 140 个家族的基因组筛选结果显示了几个新颖的感兴趣区域，以及几个重复了其他报道研究结果的区域。 根据最初的荷兰哮喘基金拨款，收集了 92 个家庭的数据，这些数据用于我们最初的分析。 根据目前的荷兰赠款，另外 108 个家庭正在接受特征分析，总共 200 个家庭已通过相同的方案进行了确定。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绘制哮喘易感基因和相关表型。