PHARMACOGENOMICS OF INHALED CORTICOSTEROID RESPONSIVENESS IN PATIENTS WITH ASTHMA

描述(申请人提供)：吸入性皮质类固醇(ICS)被认为是管理和控制持续性哮喘患者的一线治疗方法。吸入性类固醇的使用与呼吸道反应性降低、肺功能改善、症状减轻和病情恶化有关。然而，研究表明ICS反应的对象间差异很大，只有33%至50%的患者在治疗后1秒用力呼气量(FEV1)有显着改善。据估计，皮质类固醇抵抗占所有与哮喘相关的医疗费用的一半。因此，了解导致皮质类固醇耐药的因素具有重要的临床意义和经济意义。尤其是非洲裔美国患者，与白人患者相比，似乎不太可能对皮质类固醇治疗有反应。然而，目前尚不清楚这种差异是由遗传因素还是环境因素造成的，或者是否存在吸入类固醇反应性的差异(即推荐的治疗路线)。这个问题特别重要，因为非洲裔美国人患者不成比例地患有哮喘相关的并发症。到目前为止，已经有研究探讨了皮质类固醇反应性的潜在机制，但没有一项研究涉及吸入性皮质类固醇反应性，这些研究也不是为了在人群水平上识别潜在的致病遗传因素。因此，在这项应用中，我们首先计划评估非裔美国人和白人哮喘患者在吸入二碘倍氯米松(BD)治疗6周后吸入性皮质类固醇反应性(即FEV1的改善)的差异。其次，我们将寻求在接受BD治疗6周的队列中确定与ICS反应性相关的基因位点。我们队列的多样性是一个明显的优势，因为它允许我们使用关联分析和混合映射来联合识别与类固醇反应相关的基因座。接下来，我们将利用我们在患者群体中纵向评估ICS暴露和临床结果的能力，以评估同一组患者中哮喘加重(即哮喘相关急诊科就诊、哮喘相关住院和口服类固醇爆发)的药物基因组学相互作用。最后，我们将在一个单独的、更大的哮喘患者队列中验证观察到的药物x基因相互作用对哮喘恶化的影响。后一组也将来自我们筛查的哮喘人群，并将包括我们同时拥有DNA和临床数据(即，ICS历史暴露措施和临床结果)的人。因此，在这项应用中，我们计划确定一组与ICS反应性相关的基因多态，其定义为肺功能的改善和与恶化相关的临床结果的改变。

DESCRIPTION (provided by applicant): Inhaled corticosteroids (ICS) are considered first-line therapy for the management and control of patients with persistent asthma. Use of inhaled steroids has been associated with reduced airway responsiveness, improved lung function, diminished symptoms, and fewer exacerbations. However studies show considerable inter-subject variability in ICS response with only 33 per cent to 50 per cent of patients demonstrating substantial improvement in forced expiratory volume in 1 second (FEV1) following therapy. It has also been estimated that corticosteroid resistance accounts for half of all asthma-related health care costs. Therefore understanding the factors that contribute to corticosteroid resistance is both clinical and economically important. African-American patients, in particular, appear less likely to respond to corticosteroid therapy when compared with white patients. However, it is not currently known whether this difference results from genetic or environmental factors, or whether differences exist in inhaled steroid responsiveness (i.e., the recommended route of therapy). This question is of particular importance, since African-American patients suffer disproportionately from asthma-related complications. To date there have been studies examining potential mechanisms of corticosteroid responsiveness, but none have addressed inhaled corticosteroid responsiveness, nor were these studies designed to identify potentially causative genetic factors at a population-level. Therefore in this application we first plan to assess differences in inhaled corticosteroid responsiveness (i.e., improvement in FEV1) between African-American and white patients with asthma following 6 weeks of inhaled beclomethasone diproprionate (BD) treatment. Second, we will seek to identify genetic loci associated with ICS responsiveness in this cohort treated with BD for 6 weeks. The diversity of our cohort is a distinct advantage, as it allows us to use both association analysis and admixture mapping to jointly identify loci associated with steroid response. Next, we will take advantage of our ability to assess ICS exposure and clinical outcomes longitudinally in our patient population so as to assess for pharmacogenomic interactions on asthma exacerbations (i.e., asthma-related emergency department visits, asthma-related hospitalizations, and oral steroid bursts) in this same group. Lastly, we will validate observed drug x gene interactions on asthma exacerbations in a separate, larger cohort of patients with asthma. This latter group will also come from our screened asthma population and will comprise those for whom we have both DNA and clinical data (i.e., historic ICS exposure measures and clinical outcomes). Therefore, in this application we plan to identify a set of genetic polymorphisms associated with ICS responsiveness as defined by both an improvement in pulmonary function and an alteration in exacerbation-related clinical outcomes.