COLLABORATIVE STUDY OF THE GENETICS OF ASTHMA (CSGA)

哮喘遗传学合作研究 (CSGA)

• 批准号: 6183248
• 负责人: Carole Ober
• 金额: $ 72.44万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6183248
• 关键词: asthma; clinical research; cooperative study; disease /disorder proneness /risk; family genetics; gene environment interaction; genetic markers; genetic models; genetic polymorphism; genotype; human population genetics; human subject; immunologic skin test; linkage mapping; medical records; racial /ethnic difference; respiratory disorder diagnosis

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.

流行病学数据表明，哮喘的主要危险因素是 阳性家族史。 然而，赋予易感性的基因， 哮喘未知。 我们建议通过以下方法来确定哮喘易感位点： 用微卫星进行两点和复杂连锁分析 分布在整个基因组中的家族标记， 哮喘 我们的研究将集中在两个不同的样本：芝加哥内城 和郊区家庭通过儿童和成人哮喘 芝加哥大学的诊所和哈特派成员 兄弟们，一个生活在南部公共农场的宗教隔离者， 达科他州 后一种人群以前被描述为 哮喘和其他呼吸道疾病。 我们建议研究 150个诊所家庭（平均家庭规模= 10）和8个 几代同堂的哈特家族将通过以下方式选择家庭： 哮喘先证者至少有一个一级亲属， 哮喘受影响和未受影响受试者的哮喘诊断将 使用基于病史和结果的严格标准进行 肺量测定和乙酰甲胆碱激发研究。 皮肤测试通常 将进行吸入抗原检测，检测IgE水平和嗜酸性粒细胞计数 将在所有科目上进行测量。 所有的家庭成员将基因型 多达300个多态性DNA标记（微卫星标记）， 在“候选易感位点”附近或随机分布 整个基因组。 将建立永久线路或单元 来自所有科目。 基因数据的初步筛选将 使用两点连锁分析进行，考虑到两个遗传 包括疾病患病率为10并假设异质性的模型 但随着温度和比例的贡献而变化， 易感位点（20% vs. 40%）。两个点的lod得分大于 在任何遗传模型下，2.0将受到进一步的 使用非参数检验、多点连锁分析和 更复杂的遗传模型，包括额外的遗传和 环境协变量 如果发现与易感基因座的连锁， 将尝试鉴定和克隆易感性基因座。 一旦知道了易感等位基因，预防措施可以集中在 有患哮喘风险的人。 识别哮喘 易感性等位基因也有助于阐明 哮喘的原发性缺陷，并推进改善的发展 治疗。