CHARACTERIZING A 5P-LINKED BHR SUSCEPTIBILITY LOCUS

描述（改编自申请人摘要） 哮喘是工业化国家中最常见的慢性疾病， 仅在美国就有超过1000万人。 家族聚集性和一致性 同卵双胞胎的发病率表明哮喘有遗传因素。 我们 一直在进行哮喘和特应性的遗传学研究， 哈特派，一个欧洲起源的创始人人口， 生活方式 用564个标记（平均间距6cM）进行全基因组筛选， 完成了一个扩展的717哈特派血统谁是好的 其特征在于哮喘、特应性和相关表型。 这些 这些个体是生活在18世纪早期的64位祖先的后代 到19世纪初。 与支气管高反应性相关的证据2 (BHR)通过似然比 在染色体5 p上延伸超过30 cM， P值小至0.001。 在此同时， 通过传递不平衡检验（P=0.0061），位置是明显的。 在该区域中分型另外的标记物确定了2.4的关键区域 cM，对应于1.5 Mb的DNA，以及超过1.5 kb的高风险单倍型。 传播给受影响的人。 在本申请中，我们建议 通过以下方式表征哈特人中的5 p连锁BHR易感性基因座： 定位克隆和复制这些发现在远交，种族 不同的人群。我们将检查单核苷酸多态性（SNP） 在每个基因中间隔约10 kb，并评估超过10 kb的证据。 遗传给受影响的后代。 在赫特人协会将被复制在远交样品。 的 相关变体的功能效应将通过体外测定来评估 以及通过在远交样品中的基因型-表型研究， 评估哮喘和特应性表型。 识别哮喘或BHR 易感性基因座可以识别哮喘发病机制中的新途径， 从而允许开发新的疗法和干预 针对这些常见疾病的治疗方法。

DESCRIPTION (Adapted from the applicant's abstract) Asthma is the most common chronic disease in industrialized nations, affecting >10 million people in the U.S. alone. Familial aggregation and concordance rates in monozygotic twins have suggested a genetic component to asthma. We have been conducting studies on the genetics of asthma and atopy in the Hutterites, a founder population of European origins that practices a communal lifestyle. A genome-wide screen with 564 markers (average spacing 6 cM) was completed in an extended pedigree of 717 Hutterites who were well characterized with respect to asthma, atopy, and related phenotypes. These individuals are descendants of only 64 ancestors who lived in the early 1700's to the early 1800's. Evidence for linkage with bronchial hyperresponsiveness2 (BHR) by the likelihood ratio test extended over 30 cM on chromosome 5p, with P-values as small as 0.001. Additional evidence for linkage at this same location was evident by the transmission disequilibrium test (P=0.0061). Typing additional markers in this region identified a critical region of 2.4 cM, corresponding to 1.5 Mb of DNA, and a high risk haplotype that is over transmitted to affected individuals. In this application, we propose to characterize the 5p-linked BHR susceptibility locus in the Hutterites by positional cloning and to replicate these findings in outbred, ethnically diverse populations. We will examine single nucleotide polymorphisms (SNPs) spaced about 10 kb apart in each gene, and assess the evidence for over transmission to affected offspring with each SNP and SNP haplotypes. Associations in the Hutterites will be replicated in the outbred samples. The functional effects of associated variants will be assessed by in vitro assays as well as by genotype-phenotype studies in outbred samples that have been evaluated for asthma and atopy phenotypes. Identifying asthma or BHR susceptibility loci may identify novel pathways in asthma pathogenesis, thereby allowing for the development of new therapies and intervention strategies for these common diseases.