Fine mapping of an Asthma Locus of Chromosome 12q

描述(由申请人提供)： 哮喘在美国影响着1700多万人，并继续是美国发病率的一个重要原因。大量证据表明，哮喘是一种复杂的遗传疾病，人们希望对哮喘遗传决定因素的识别将有助于更好地了解哮喘的病理生物学，并可能导致新的预防策略和治疗方案的开发。为此，世界各地的许多研究小组进行了全基因组连锁扫描，试图确定哮喘易感性增加的区域。染色体12Q着丝粒区域是证明与哮喘有关联的最常见的区域之一(在已发表的11项研究中有6项)。我们假设在染色体12Q上存在一个哮喘易感基因，并且该基因可以通过高分辨率单核苷酸多态(SNP)定位策略来识别。我们提出了一个识别该基因座的三阶段计划。在第一阶段，我们将在两个DNA池样本中筛选大约1500个SNPs：一个DNA池来自护士健康研究(NHS)确认的394名哮喘患者，另一个池匹配的健康对照。我们将筛选病例和对照组之间存在显著等位基因频率差异的证据，并确定与哮喘表型相关的SNPs(“阳性SNPs”)。在第二阶段，我们将通过对NHS个人DNA样本中的“阳性SNPs”进行基因分型来验证我们在第一阶段的发现。个体样本的基因分型将允许更准确地估计等位基因频率，并使明确的病例对照关联分析以及单倍型归因成为可能。在第三阶段，我们将在460名哮喘子女及其父母通过儿童哮喘管理计划(CAMP)获得的以家庭为基础的队列中复制NHS哮喘队列的发现。CAMP具有广泛的表型信息，包括肺功能、呼吸道反应性和特应性相关特征的评估。我们将在460个哮喘三组中验证第二阶段的SNPs，并使用哮喘表型和中间数量性状进行基于家族的关联分析。我们期望在NHS和CAMP队列中识别与哮喘相关的SNPs，这代表了重要的哮喘易感性SNPs。这些变异的识别可能会对哮喘患者的公共健康产生重大影响。

DESCRIPTION (provided by applicant): Bronchial asthma affects over 17 million people in the United States and continues to be a significant cause of morbidity in the U.S. There is substantial evidence that asthma is a complex genetic disorder, and there is hope that identification of the genetic determinants of asthma will lead to a better understanding of asthma pathobiology and potentially lead to the development of new preventative strategies and treatment regimens. Towards this end, many groups around the world have performed genome-wide linkage scans in an attempt to identify regions conferring heightened asthma-susceptibility. The centromeric region of chromosome 12q is one of the most frequently identified regions demonstrating evidence for linkage with asthma (in 6 of 11 published studies). We hypothesize that an asthma-susceptibility gene exists on chromosome 12q, and that this gene can be identified using a high-resolution single nucleotide polymorphism (SNP) mapping strategy. We propose a three-stage plan to identify this locus. In stage 1, we will screen approximately 1,500 SNPs in two samples of pooled DNA: one DNA pool from 394 asthmatics identified in the Nurses Health Study (NHS) and one pool of matched healthy controls. We will screen for evidence of significant allele-frequency differences between the case and control pools and identify SNPs that are associated with the asthma phenotype ("positive-SNPs"). In stage 2, we will validate our findings from stage 1 by genotyping the "positive-SNPs" in the individual DNA samples from the NHS. Genotyping of individual samples will allow for more accurate estimation of allele frequency and to enable explicit case-control association analysis, as well as haplotype imputation. In stage 3, we will replicate findings from the NHS asthma cohort in a family-based cohort of 460 asthmatic offspring and their parents obtained through the Childhood Asthma Management Program (CAMP). CAMP has extensive phenotypic information including assessment of lung function, airways responsiveness and atopy-related traits. We will validate SNPs from stage 2 in 460 asthma trios and perform family-based association analyses using both the asthma phenotype and intermediate quantitative traits. We anticipate identifying SNPs associated with asthma in both the NHS and CAMP cohorts, representing important asthma-susceptibility SNPs. Identification of these variants may have a significant impact on the public health of asthma patients.