POSITIONAL CANDIDATE GENE APPROACHES IN ASTHMA GENE DISC

描述(改编自申请人的摘要) 拟议的项目利用了人类快速发展的优势 基因组计划(HGP)用于识别位置候选基因，其基础是 我们正在进行的哮喘基因图谱研究和2756名患者的现存DNA样本 至少有两个兄弟姐妹患有医生诊断的哮喘的核心家庭 和合适的父母。我们基于全基因组扫描的初步分析 435个兄弟姐妹均出现乙酰甲胆碱阳性的家庭 挑战测试已经确定了两个与 哮喘相关表型。22号染色体上D22S926附近的区域是 与FEV1显著相关。我们初步确定了6-7名候选人 两个连锁区中每一个的基因。随着人类基因组计划的完成和 在不久的将来提供更详细的基因注释，列表 位置候选基因将会增长。我们假设一个或多个 我们列表上的位置候选基因与哮喘中间体相关 与候选区域有显著联系的表型。我们有 确定了675个至少有一个兄弟姐妹乙酰甲胆碱阳性的家庭 激发试验(PD20小于或等于？16毫克)和高外周血 嗜酸性粒细胞计数(第一组)和909个至少有两个的家庭 提供FEV1测量的兄弟姐妹(Panel II系列)以测试我们的 使用基于家庭的关联检验(FBAT)的假设。DHPLC方法， 一项最先进的突变检测技术，将被用于快速 发现足够数量的新的单核苷酸多态标记 (SNPs)在选定的位置候选基因中。常见的多态现象 的候选基因将使用寡核苷酸连接进行基因分型 化验(OLA)。整合来自两个或多个SNP基因座的信息 在我们的分析中，多个相关基因和环境风险因素，我们 还将评估单倍型的贡献，并测试基因- 除了单基因座分析外，还有环境交互作用。有两个 这项建议的特点是：(1)两个拟议区域的联系 有重大意义；以及(2)我们的大样本确保了足够的能力 检测关联。凭借我们在流行病学方面的专业知识，临床 医学、分子遗传学、生物统计学和人口资源，我们 有信心我们可以推进对基因的理解 哮喘的决定因素。拟议中的研究结果可能会导致 改进了预防、诊断和治疗这种疾病的战略。 (摘要结束。)

DESCRIPTION (Adapted from the applicant's abstract) The proposed project takes advantage of the rapid progression of the Human Genome Project (HGP) in identifying positional candidate genes and is built on our ongoing asthma gene-mapping study and existent DNA samples in 2,756 nuclear families with at least two siblings with physician-diagnosed asthma and available parents. Our preliminary analysis based on a genome-wide scan on 435 families with both siblings experiencing a positive methacholine challenge test has identified two regions that are significantly linked to asthma related phenotypes. The region near D22S926 on chromosome 22 is significantly linked to FEV1. We have initially identified 6-7 candidate genes in each of the two linkage regions. With the completion of the HGP and availability of more detailed gene annotation in the near future, the list of positional candidate genes will grow. We hypothesize that one or more of the positional candidate genes on our list is associated with asthma intermediate phenotypes with significant linkages to the candidate regions. We have identified 675 families with at least one sibling with a positive methacholine challenge test (PD20 less than or equal to? 16 mg) and high peripheral blood eosinophil count (Panel I Families), and 909 families with at least two siblings with FEV1 measurements available (Panel II Families) to test our hypothesis using the family based association test (FBAT). The DHPLC method, a state-of-the-art mutation detection technology, will be used to rapidly discover a sufficient number of novel single nucleotide polymorphism markers (SNPs) in the selected positional candidate genes. The common polymorphisms of selected candidate genes will be genotyped using oligonucleotide ligation assay (OLA). To incorporate information from two or more SNP loci from multiple related genes and from environmental risk factors in our analyses, we will also assess the contribution of haplotypes and test gene-gene and gene- environment interactions in addition to single locus analysis. There are two unique features to this proposal: (1) the linkages in the two proposed regions are significant; and (2) our large sample size assures adequate power to detect the association. With our expertise in epidemiology, clinical medicine, molecular genetics, biostatistics, and the population resources, we are confident that we can advance the understanding of the genetic determinants of asthma. The findings from the proposed study may lead to improved strategies for prevention, diagnosis, and treatment of this disease. (End of Abstract.)