Asthma Candidate Genes in Alpha 1-Antitrypsin Deficiency

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是一种严重的公共卫生问题。吸烟是疾病的主要环境危险因素，但在吸烟者中，气流阻塞的发展是不同的。慢性阻塞性肺病可能是一种遗传复杂的疾病，但α 1-抗胰蛋白酶（AAT）缺乏是唯一已知的慢性阻塞性肺病的遗传危险因素。在严重AAT缺乏（基因型PI ZZ）的个体中，肺功能下降也存在变异性，这表明存在与疾病发生和进展相关的其他遗传因素。一部分COPD患者也会有哮喘的表现。我们假设与哮喘和哮喘相关表型相关的基因是严重AAT缺乏症患者COPD表达的修饰因子。通过资助的NIH项目“α 1-抗胰蛋白酶缺乏症的遗传修饰因子”（RO1 HL 68926），正在收集400个家庭，其中包括至少两个成年PI ZZ兄弟姐妹。我们建议研究这些家族中的哮喘表型和哮喘候选基因多态性，使用候选基因方法和基于家族的关联测试进行分析，以追求三个不同的假设，1)。我们假设哮喘表型在PI ZZ AAT缺乏个体中很常见，并且可能因年龄、性别和肺功能水平而改变。2)我们假设哮喘候选基因多态性与PI ZZ个体的哮喘表型相关。3)我们假设哮喘候选基因多态性与PI ZZ个体的COPD表型相关。基于家族的哮喘候选基因关联分析是对正在进行的项目的补充，该项目使用基因组扫描和连锁分析来识别该人群中COPD的修饰基因。了解AAT缺乏症患者肺部疾病的调节因素可能对预后和治疗有重要影响。确定AAT缺乏症COPD的调节因素可能对无AAT缺乏症COPD患者具有重要的公共卫生相关性。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is a disease of tremendous public health concern. Cigarette smoking is the major environmental risk for disease, but the development of airflow obstruction is variable amongst smokers. COPD is likely a genetically complex disease, but alpha 1-antitrypsin (AAT) deficiency is the only known genetic risk factor for COPD. Variability in lung function decline also exists among individuals with severe AAT deficiency (genotype PI ZZ), suggesting the presence of other genetic factors relevant to disease development and progression. A subset of individuals with COPD will also have manifestations of asthma. We hypothesize that genes associated with asthma and asthma-related phenotypes represent modifying factors for the expression of COPD in individuals with severe AAT deficiency. Through the funded NIH project "Genetic Modifiers of Alpha 1-Antitrypsin Deficiency" (RO1 HL 68926), 400 families are being collected that include at least two adult PI ZZ siblings. We propose to investigate asthma phenotypes and asthma candidate gene polymorphisms in these families, using a candidate gene approach and family-based association tests for analysis, to pursue three distinct hypotheses, 1). We hypothesize that asthma phenotypes are common in PI ZZ AAT deficient individuals, and may be modified by age, sex, and level of lung function. 2) We hypothesize that asthma candidate gene polymorphisms are associated with asthma phenotypes in PI ZZ individuals. 3) We hypothesize that asthma candidate gene polymorphisms are associated with COPD phenotypes in PI ZZ individuals. Family-based association analysis of asthma candidate genes in a population enriched to develop COPD from a major gene effect will be complementary to the ongoing project that uses genome scanning and linkage analysis to identify modifier genes for COPD in this population. Understanding modifying factors for lung disease in individuals with AAT deficiency will potentially have important prognostic and therapeutic impact. The identification of modifying factors of COPD in AAT deficiency may have significant public health relevance to COPD patients without AAT deficiency.