Genetics of Asthma and Bronchial Hyperresponsiveness

哮喘和支气管高反应性的遗传学

• 批准号: 7235592
• 负责人: Deborah A. Meyers
• 金额: $ 49.38万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7235592
• 关键词: 5q31; ARHGEF5 gene; Area; Asthma; Biological; Candidate Disease Gene; Caucasians; Caucasoid Race; Characteristics; Chicago; Child; Chromosomes; Clinical; Clinical Data; Collaborations; Condition; DNA; Data; Data Set; Databases; Development; Disease; Doctor of Philosophy; Environmental Exposure; Environmental Risk Factor; Ethnic group; Evaluation; Exposure to; Family; Family member; Funding; Genes; Genetic; Genome; Genomics; Genotype; Haplotypes; Hypersensitivity; IL4 gene; IgE; Inflammatory; Interleukin-4; Knowledge; Letters; Life; Link; Linkage Disequilibrium; Location; Maps; Measures; Microsatellite Repeats; Mus; Netherlands; Numbers; Parents; Passive Smoking; Phenotype; Population; Positioning Attribute; Progress Reports; Publishing; Pulmonary Function Test/Forced Expiratory Volume 1; Questionnaires; Regulation; Relative (related person); Research; Research Personnel; Resources; Respiratory physiology; Risk; Role; SNP genotyping; Sample Size; Sampling; Series; Serum; Severities; Single Nucleotide Polymorphism Map; Structure; Susceptibility Gene; Testing; Time; Tissues; Universities; Variant; Work; atopy; base; case control; chromosome 5q loss; cigarette smoking; cigarette smoking; cytokine; demographics; forest; gene environment interaction; genetic analysis; genetic linkage analysis; hutterite; positional cloning; proband; professor; programs; pulmonary function; trait

DESCRIPTION (provided by applicant): Asthma is an inflammatory airways disease caused by an interaction between susceptibility genes for asthma and atopy and a diverse group of environmental exposures. It appears that there is no single susceptibility gene that confers major risk, but more likely a series of genes with interactive effects that increase the risk for asthma and/or other atopic conditions after exposure to specific environmental factors. We have collected a well-characterized Dutch asthma population of 200 families, which has been recently expanded to include an additional 437 trios with bronchial hyperresponsiveness (BHR), 366 of whom have clinical asthma. These two samples of Dutch families form the basis for this competitive renewal. We have been collaborating with Professor Dirkje S Postma MD, PhD and her colleagues at the University of Groningen, the Netherlands for over 10 ten years. Our studies on this homogeneous Dutch population from northern Holland ascertained through a parent with asthma who was originally characterized approximately 25 years previously have been very productive. We hypothesize that important susceptibility genes for asthma and atopy map to chromosomes 2q and 5q where we have strong evidence for linkage. To investigate this, we will continue positional cloning approaches for these two chromosomes in conjunction with positional candidate gene association studies using both our Dutch families and trios, with the evaluation of gene-environment interactions (exposure to passive smoking). The specific aims of this proposal are: 1) Complete the phenotypic data set on the new 437 trios and perform analyses of their clinical characteristics for comparison with the family population 2) Identify genes on chromosome 2q related to asthma for two phenotypes: FEV1/VC and total serum IgE levels using a combination of positional cloning and positional candidate gene approaches in the Dutch trios and families, 3) Identify susceptibility genes for asthma and BNR on chromosome 5q31-33 using a combination of positional cloning and positional candidate gene approaches in the Dutch trios and families, 4) Evaluate asthma susceptibility genes to determine significance in our Dutch populations and their potential role in asthma severity (progression of asthma) using the longitudinal data on the 200 probands. These scientific approaches will allow us to prioritize candidate genes based on available knowledge of map position and biological relevance, obtain genomic structure and study sequence variants in our populations to facilitate the identification of genes that are important in the development of asthma and associated phenotypes.

描述（由申请人提供）：哮喘是一种炎症性气道疾病，由哮喘和特应性的易感基因与多种环境暴露之间的相互作用引起。似乎没有单一的易感基因赋予主要风险，但更有可能是一系列具有交互作用的基因，在暴露于特定环境因素后增加哮喘和/或其他特应性疾病的风险。我们收集了200个家庭的荷兰哮喘人群，最近已扩大到包括额外的437个三人组与支气管高反应性（BHR），其中366人有临床哮喘。这两个荷兰家庭的样本构成了这种竞争性更新的基础。我们与荷兰格罗宁根大学的Dirkje S Postma博士和她的同事合作了10多年。我们对来自荷兰北方的同质荷兰人群的研究非常富有成效，这些研究是通过父母患有哮喘而确定的，该哮喘最初是在大约25年前确定的。我们假设哮喘和特应性的重要易感基因映射到染色体2 q和5 q，我们有强有力的证据表明这些基因存在连锁关系。为了研究这一点，我们将继续定位克隆方法，这两个染色体结合位置候选基因关联研究，使用我们的荷兰家庭和三人组，与基因环境相互作用的评价（暴露于被动吸烟）。该提案的具体目的是：1）完成新的437个三人组的表型数据集，并对其临床特征进行分析，以与家族人群进行比较2）鉴定染色体2 q上与两种表型哮喘相关的基因：在荷兰三人组和家庭中使用位置克隆和位置候选基因方法相结合的FEV 1/VC和总血清IgE水平，3）在荷兰三人组和家庭中使用定位克隆和定位候选基因方法的组合来鉴定染色体5 q31 -33上的哮喘和BNR的易感基因。4）使用200个先证者的纵向数据来评价哮喘易感基因以确定在我们荷兰人群中的显著性及其在哮喘严重性（哮喘进展）中的潜在作用。这些科学方法将使我们能够根据图谱位置和生物相关性的现有知识优先考虑候选基因，获得基因组结构并研究我们人群中的序列变异，以促进识别在哮喘和相关表型发展中重要的基因。

项目成果

Evidence for two unlinked loci regulating total serum IgE levels.

两个不连锁基因座调节总血清 IgE 水平的证据。

• 发表时间: 1995
• 期刊: American journal of human genetics
• 影响因子: 9.8
• 作者: Xu,J;Levitt,RC;Panhuysen,CI;Postma,DS;Taylor,EW;Amelung,PJ;Holroyd,KJ;Bleecker,ER;Meyers,DA
• 通讯作者: Meyers,DA

Differential desensitization of homozygous haplotypes of the beta2-adrenergic receptor in lymphocytes.

淋巴细胞中β2-肾上腺素能受体纯合单倍型的差异脱敏。

• DOI: 10.1164/rccm.200409-1162oc
• 发表时间: 2005
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Oostendorp,Jaap;Postma,DirkjeS;Volders,Haukeline;Jongepier,Hajo;Kauffman,HenkF;Boezen,HMarike;Meyers,DeborahA;Bleecker,EugeneR;Nelemans,SAdriaan;Zaagsma,Johan;Meurs,Herman
• 通讯作者: Meurs,Herman

Localization of the A3 adenosine receptor gene (ADORA3) to human chromosome 1p.

A3 腺苷受体基因 (ADORA3) 定位于人类染色体 1p。

• DOI: 10.1016/0888-7543(95)80194-q
• 发表时间: 1995
• 期刊: Genomics
• 影响因子: 4.4
• 作者: Monitto,CL;Levitt,RC;DiSilvestre,D;Holroyd,KJ
• 通讯作者: Holroyd,KJ

Fluorescence-based resource for semiautomated genomic analyses using microsatellite markers.

使用微卫星标记进行半自动基因组分析的基于荧光的资源。

• DOI: 10.1006/geno.1994.1628
• 发表时间: 1994
• 期刊: Genomics
• 影响因子: 4.4
• 作者: Levitt,RC;Kiser,MB;Dragwa,C;Jedlicka,AE;Xu,J;Meyers,DA;Hudson,JR
• 通讯作者: Hudson,JR

Approaches to mapping genes for allergy and asthma.

绘制过敏和哮喘基因图谱的方法。

• DOI: 10.1164/ajrccm.152.1.7599858
• 发表时间: 1995
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Meyers,DA;Bleecker,ER
• 通讯作者: Bleecker,ER