CHARACTERIZING A 5P-LINKED BHR SUSCEPTIBILITY LOCUS

描述(改编自申请人的摘要) 哮喘是工业化国家最常见的慢性疾病，影响 仅在美国，就有1000万人。家庭聚集性与和谐 同卵双胞胎的比率表明哮喘是一个遗传因素。我们 一直在对哮喘和特应性疾病的遗传学进行研究 Hutterites，一个起源于欧洲的创始群体，实行公社 生活方式。有564个标记的全基因组筛选(平均间距6 cM)是 在717名哈特利人中完成，他们都很好 以哮喘、特应性和相关的表型为特征。这些 个人只是生活在17世纪初的祖先S的后代 至19世纪初的S。与支气管高反应性有关的证据2 (Bhr)经5p染色体上30 cM以上的似然比检验， P值低至0.001。更多的证据证明了这一点 经传递不平衡检验，定位明显(P=0.0061)。 在该区域输入其他标记确定了2.4的关键区域 Cm，相当于1.5Mb的DNA，以及结束的高危单倍型 传播给受影响的个人。在本申请中，我们建议 Hutterite人群中5P连锁的BHR易感基因的特征 位置克隆，并将这些发现复制到远缘繁殖的种族中 不同的人群。我们将研究单核苷酸多态(SNPs) 在每个基因上间隔约10kb，并评估超过 以每种SNP和SNP单倍型传递给患病后代。 Hutterite人中的联合将在远缘繁殖的样本中复制。这个 相关变异的功能效应将通过体外试验进行评估 以及通过对异种繁殖样本进行的基因表型研究 评估哮喘和过敏症的表型。识别哮喘或BHR 易感基因座可能识别哮喘发病机制中的新途径， 从而允许开发新的治疗方法和干预 针对这些常见疾病的策略。

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.