Van Eerdewegh Paul, Little Randall D, Dupuis Josée, Del Mastro Richard G, Falls Kathy, Simon Jason, Torrey Dana, Pandit Sunil, McKenny Joyce, Braunschweiger Karen, Walsh Alison, Liu Ziying, Hayward Brooke, Folz Colleen, Manning Susan P, Bawa Alicia, Saracino Lisa, Thackston Michelle, Benchekroun Youssef, Capparell Neva, Wang Mei, Adair Ron, Feng Yun, Dubois JoAnn, FitzGerald Michael G, Huang Hui, Gibson René, Allen Kristina M, Pedan Alex, Danzig Melvyn R, Umland Shelby P, Egan Robert W, Cuss Francis M, Rorke Steuart, Clough Joanne B, Holloway John W, Holgate Stephen T, Keith Tim P
Genome Therapeutics Corporation, 100 Beaver St, Waltham, Massachusetts 02453, USA.
Nature. 2002 Jul 25;418(6896):426-30. doi: 10.1038/nature00878. Epub 2002 Jul 10.
Asthma is a common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component. To date, linkage studies have identified more than a dozen genomic regions linked to asthma. In this study, we performed a genome-wide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (log(10) of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene as being significantly associated with asthma using case-control, transmission disequilibrium and haplotype analyses (P = 0.04 0.000003). ADAM proteins are membrane-anchored metalloproteases with diverse functions, which include the shedding of cell-surface proteins such as cytokines and cytokine receptors. The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease.
哮喘是一种常见的呼吸系统疾病，其特征为反复出现咳嗽、喘息和呼吸急促。尽管诸如接触过敏原等环境因素是哮喘发病的危险因素，但双胞胎研究和家族研究均表明其有很强的遗传成分。迄今为止，连锁研究已确定了十几个与哮喘相关的基因组区域。在本研究中，我们对460个白种人家庭进行了全基因组扫描，在20号染色体p13区域确定了一个与哮喘（对数似然比（LOD）为2.94）和支气管高反应性（LOD为3.93）相关的基因座。通过对23个基因中的135个多态性进行调查，采用病例对照、传递不平衡和单倍型分析，确定ADAM33基因与哮喘显著相关（P = 0.04至0.000003）。ADAM蛋白是具有多种功能的膜锚定金属蛋白酶，包括脱落细胞表面蛋白，如细胞因子和细胞因子受体。通过在远交群体中进行定位克隆鉴定出的一个假定的哮喘易感基因ADAM33的鉴定和表征，应为深入了解这种常见疾病的发病机制和自然史提供线索。
