Asthma Candidate Genes in Alpha 1-Antitrypsin Deficiency

描述(申请人提供)：慢性阻塞性肺疾病(COPD)是一种极具公共卫生意义的疾病。吸烟是导致疾病的主要环境风险，但不同吸烟者发生气流阻塞的情况各不相同。COPD可能是一种基因复杂的疾病，但α1-抗胰蛋白酶(AAT)缺乏是COPD唯一已知的遗传风险因素。在AAT严重缺乏的个体(PiZZ)中也存在肺功能下降的变异性，这表明存在与疾病发生和进展相关的其他遗传因素。COPD患者的一部分也会有哮喘的表现。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。通过国立卫生研究院资助的项目“阿尔法1-抗胰蛋白酶缺乏症的遗传修饰者”(RO1 HL 68926)，收集了400个家庭，其中至少包括两个成年的PiZZ兄弟姐妹。我们建议调查这些家系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庭的关联检验进行分析，以追求三个不同的假设：1)。我们推测，哮喘表型在PiZZ AAT缺陷个体中很常见，可能会受到年龄、性别和肺功能水平的影响。2)我们假设哮喘候选基因多态与皮下ZZ人群的哮喘表型相关。3)我们假设哮喘候选基因多态与皮下ZZ人群的COPD表型相关。对哮喘候选基因的家族关联分析将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确定该人群中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会对预后和治疗产生重要影响。识别AAT缺乏的COPD的修饰因素可能对无AAT缺乏的COPD患者具有显著的公共卫生意义。

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.