Genetic studies in difficult to treat asthma: TENOR

描述（由申请人提供）：TENOR（哮喘的流行病学和自然史：结局和治疗方案）研究是一项正在进行的为期三年的多中心观察性队列研究，研究对象为4756名6岁或以上的重症或难治性哮喘患者。在这组哮喘患者中，44.6%的患者符合NHLBI NAEPP指南的重度持续性哮喘，27.5%的患者符合中度持续性哮喘，27.8%的患者符合轻度持续性哮喘。所有受试者最初通过全面的问卷调查和实验室测试进行评估，然后在剩余的3年研究中每6个月进行一次检查。收集的表型信息包括哮喘加重、药物使用、急诊就诊、生活质量、肺功能测试（可逆性肺活量测定法）、血清总IgE水平和过敏史。在TENOR研究结束之前，如果现在访问该人群，该人群代表了基因组和药物遗传学研究中具有表型特征的难治性和重度哮喘患者的最大人群之一。TENOR将于2004年底结束，因此我们在研究结束前获得用于遗传研究的DNA样本的时间窗口非常短。从这一具有良好特征的纵向人群中分离和储存DNA不仅将为本基金提出的研究提供资源，而且还将为未来哮喘基因组学和药物遗传学研究提供资源。我们建议研究影响哮喘严重程度的遗传因素，在这个特征明确的大哮喘人群中。我们假设，产生难治和严重哮喘的因素是由炎症反应改变产生的，至少部分与调节炎症、过敏反应和/或影响气道结构成分的基因序列变异（多态性）有关。我们还假设一些患者发展为更严重的哮喘，因为基因差异调节了他们对药物的反应。为了验证这些假设，我们提出以下具体目标：1)从至少4000名目前正在进行的TENOR研究中登记的哮喘患者中获取DNA样本；2)使用基线数据确定调节炎症、细胞反应和/或组织损伤和修复的基因序列变异（多态性）是否更频繁地与哮喘严重程度相关；3)确定在这类难治性哮喘患者中可能对IgE调节有重要作用的基因的遗传多态性的重要性；4)评估长效β -2激动剂受试者中¿2肾上腺素能受体（¿2AR）多态性之间的药理学关系，以确定对哮喘严重程度的影响；5)通过研究调节哮喘治疗反应的基因多态性是否在严重疾病中更常见来评估药理学机制。

DESCRIPTION (provided by applicant): The TENOR (The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens) study is an ongoing three-year multi-center observational cohort study of 4756 severe or difficult-to-treat patients with asthma aged 6 or older. Of this group of asthmatics, 44.6% meet the NHLBI NAEPP guidelines for severe persistent asthma, 27.5% for moderate persistent asthma, and 27.8% for mild persistent asthma. All subjects were evaluated initially with comprehensive questionnaires and laboratory testing, and are then seen every 6 months during the remaining 3 years of the study. Phenotypic information collected includes information on asthma exacerbations, medication use, urgent care visits, quality of life, pulmonary function tests (spirometry with reversibility), total serum IgE levels, and history of allergies. If accessed now, before the termination of the TENOR study, this population represents one of the largest populations of phenotypically characterized difficult-to-treat and severe asthmatics potentially available for genomic and pharmacogenetic studies. TENOR will finish at the end of 2004, thus we have a very short time window in which to obtain DNA samples for genetic studies before the termination of the study. Isolation and storage of DNA from this well characterized, longitudinal population will serve as a resource not only for the proposed studies in this grant but also for future genomics and pharmacogenetic studies in asthma. We propose to investigate genetic factors that affect asthma severity in this well-characterized, large asthma population. We hypothesize that factors which produce difficult-to-treat and severe asthma are produced by altered inflammatory responses that are related, at least in part, to sequence variants (polymorphisms) in genes that regulate inflammation, allergic responsiveness, and/or affect structural components in the airways. We also hypothesize that some patients develop more severe asthma because of genetic differences that modulate their responses to pharmacologic agents. To test these hypotheses, we propose the following specific aims: 1) Obtain DNA samples from at least 4,000 asthmatics currently enrolled in the ongoing TENOR study; 2) Determine whether sequence variants (polymorphisms) in genes that regulate inflammation, cellular responses, and/or tissue injury and repair are more frequently associated with asthma severity using the baseline data; 3) Determine the importance of genetic polymorphisms in genes that may be important in IgE regulation in this population of difficult-to-treat patients with asthma; 4) Evaluate pharmacogenetic relationships between polymorphisms in the ¿2 adrenergic receptor (¿2AR) in those subjects on long-acting beta-2-agonists to determine the effect on asthma severity; 5) Evaluate pharmacologic mechanisms by investigating whether polymorphisms in genes that regulate responses to asthma therapy are more frequent in severe disease.