PHARMACOGENOMICS OF INHALED CORTICOSTEROID RESPONSIVENESS IN PATIENTS WITH ASTHMA

描述（由申请人提供）：吸入皮质类固醇（ICS）被认为是管理和控制持续性哮喘患者的一线治疗方法。使用吸入类固醇可降低气道反应性，改善肺功能，减轻症状，减少病情恶化。然而，研究显示ICS反应的受试者间差异很大，只有33%至50%的患者在治疗后1秒用力呼气量（FEV1）有实质性改善。据估计，皮质类固醇耐药性占所有哮喘相关医疗保健费用的一半。因此，了解导致皮质类固醇抵抗的因素在临床和经济上都很重要。尤其是非裔美国患者，与白人患者相比，对皮质类固醇治疗的反应似乎更少。然而，目前尚不清楚这种差异是遗传因素还是环境因素造成的，或者吸入类固醇反应性（即推荐的治疗途径）是否存在差异。这个问题尤其重要，因为非裔美国人患者患哮喘相关并发症的比例过高。迄今为止，已有研究考察了皮质类固醇反应性的潜在机制，但没有研究涉及吸入皮质类固醇反应性，也没有研究旨在确定人群水平上潜在的致病遗传因素。因此，在本应用中，我们首先计划评估非裔美国人和白人哮喘患者在吸入双proprionate倍氯米松（BD）治疗6周后吸入皮质类固醇反应性（即FEV1的改善）的差异。其次，我们将在接受双相障碍治疗6周的队列中寻找与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共同识别与类固醇反应相关的位点。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，以评估同一组哮喘加重（即哮喘相关急诊就诊、哮喘相关住院和口服类固醇发作）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加重的影响。后一组也将来自我们筛选的哮喘人群，包括我们拥有DNA和临床数据（即历史ICS暴露测量和临床结果）的人群。因此，在本应用中，我们计划确定一组与ICS反应性相关的遗传多态性，该多态性由肺功能的改善和与恶化相关的临床结果的改变来定义。公共卫生相关性：吸入皮质类固醇（ICS）被认为是持续性哮喘的一线治疗方法，但对影响这种治疗反应的遗传因素知之甚少。这已经

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. PUBLIC HEALTH RELEVANCE: Inhaled corticosteroids (ICS) are considered first-line treatment for persistent asthma, yet little is known about the genetic factors that influence response to this therapy. This has particular importance to African American patients who suffer disproportionately from asthma complications and who may be less likely to respond to treatment. This study seeks to quantify response to ICS therapy in African American and white patients, as well as use cutting-edge genetic techniques to look for markers that predict treatment response. Knowledge gained from this study may help clinicians select asthma treatments most likely to work for their patients, as well as provide insight for future asthma therapeutics.