COLLABORATIVE STUDY OF THE GENETICS OF ASTHMA (CSGA)

流行病学数据表明，哮喘的一个主要危险因素是 有积极的家族史。然而，导致癌症易感性的基因 哮喘是未知的。我们建议通过以下方法确定哮喘易感基因 利用微卫星进行两点复合连锁分析 标记分布在定义明确的家系的整个基因组中 哮喘。我们的研究将集中在两个不同的样本上：芝加哥市中心 和郊区家庭通过儿童和成人哮喘确诊 芝加哥大学的诊所和哈特利派成员 兄弟会，一种生活在南方公共农场的宗教孤立 达科他州。后一种人群以前的特征是 对哮喘和其他呼吸道疾病的尊重。我们建议研究 150个诊所家庭(平均家庭人数=10人)和8个 代代相传的哈特利家族。将通过以下方式选择族 至少有一个一级亲属的哮喘先证者 哮喘。在受影响和未受影响的受试者中诊断哮喘将 使用基于病史和结果的严格标准进行 肺活量测定法和乙酰甲胆碱挑战研究。常见的皮肤测试 将进行吸入抗原、IgE水平和嗜酸性粒细胞计数 将在所有科目上进行测量。所有家庭成员都将是基因型 多达300个多态DNA标记(微卫星标记) 接近“候选易感基因座”或随机分布 在整个基因组中。将建立永久线路或单元格 源自所有科目。对遗传数据的初步筛选将是 使用两点连锁分析，考虑两个基因 包含疾病流行率为10并假定异质性的模型 但在外显率和比例贡献方面有所不同 易感基因座(20%vs.40%)。LOD得分高出两分 在任何遗传模型下都将受到进一步的 使用非参数检验、多点关联分析和 更复杂的遗传模型，融合了额外的遗传和 环境协变量。如果发现与易感基因连锁， 将尝试识别和克隆易感基因。 一旦知道易感等位基因，预防措施就可以集中在 有患哮喘风险的个人。辨证哮喘 易感等位基因也有助于阐明 原发缺陷与哮喘的发展改良 治疗。

Epidemiologic data indicate that a major risk factor for asthma is a positive family history. However, genes that confer susceptibility to asthma are unknown. We propose to identify asthma susceptibility loci by performing two-point and complex linkage analysis with microsatellite markers distributed throughout the genome in families with well-defined asthma. Our study will focus on two distinct samples: Chicago inner-city and suburban families ascertained through the pediatric and adult asthma clinics at the University of Chicago and members of the Hutterite brethren, a religious isolate that lives on communal farms in South Dakota. The latter population has previously been characterized with respect to asthma and other respiratory illnesses. We propose to study 150 clinic families (average family size = 10) and eight multigenerational Hutterite families. Families will be selected through asthmatic probands who have at least one first degree relative with asthma. The diagnosis of asthma in affected and unaffected subjects will be made using strict criteria based on medical history and results of spirometry and methacholine challenge studies. Skin tests for commonly inhaled antigens will be performed, and IgE levels and eosinophil counts will be measured on all subjects. All family members will be genotype for up to 300 polymorphic DNA markers (microsatellite markers) that map near "candidate susceptibility loci" or are distributed randomly throughout the genome. Permanent lines will be established or cells derived from all subjects. Preliminary screening of genetic data will be performed using two-point linkage analysis, considering two genetic models that include a disease prevalence of 10 and assume heterogeneity but vary with respect to penetrance and the proportional contribution of the susceptibility locus (20% vs. 40%). A two-point lod score greater than 2.0 under any genetic model will be subjected to further investigation using nonparametric tests, multipoint linkage analysis, and more sophisticated genetic models that incorporate additional genetic and environmental covariates. If linkage to a susceptibility locus is found, attempts will be make to identify and clone the susceptibility locus. Once susceptibility alleles are known, preventive measures can focus on individuals at-risk for developing asthma. Identifying asthma susceptibility alleles would also contribute toward elucidating the primary defect in asthma and advance the development of improved treatments.