PHARMACOGENOMICS OF INHALED CORTICOSTEROID RESPONSIVENESS IN PATIENTS WITH ASTHMA

描述（由申请方提供）：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。使用吸入性类固醇与气道反应性降低、肺功能改善、症状减轻和急性加重减少有关。然而，研究显示ICS反应的受试者间差异相当大，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，皮质类固醇抵抗占所有哮喘相关医疗费用的一半。因此，了解导致皮质类固醇耐药的因素在临床和经济上都很重要。特别是非洲裔美国患者，与白色患者相比，对皮质类固醇治疗的反应更少。然而，目前尚不清楚这种差异是否由遗传或环境因素引起，或者吸入类固醇反应性是否存在差异（即，推荐的治疗方法）。这个问题特别重要，因为非洲裔美国患者患哮喘相关并发症的比例不成比例。到目前为止，已经有研究检查皮质类固醇反应性的潜在机制，但没有解决吸入皮质类固醇反应性，也没有这些研究旨在确定潜在的致病遗传因素在人群水平。因此，在本申请中，我们首先计划评估吸入性皮质类固醇反应性的差异（即，非裔美国人和白色哮喘患者在吸入二丙酸倍氯米松（BD）治疗6周后FEV1）的改善。第二，我们将在接受BD治疗6周的队列中寻找与ICS反应性相关的遗传基因座。我们的队列的多样性是一个明显的优势，因为它使我们能够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基因座。接下来，我们将利用我们在患者人群中纵向评估ICS暴露和临床结局的能力，以评估哮喘急性发作的药物基因组学相互作用（即，哮喘相关的急诊就诊、哮喘相关的住院治疗和口服类固醇爆发）。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急性发作的影响。后一组也将来自我们筛选的哮喘人群，并将包括我们拥有DNA和临床数据的人群（即，历史ICS暴露测量和临床结果）。因此，在本申请中，我们计划确定一组与ICS反应性相关的遗传多态性，其定义为肺功能改善和急性加重相关临床结局的改变。公共卫生相关性：吸入性皮质类固醇（ICS）被认为是持续性哮喘的一线治疗，但对影响这种治疗反应的遗传因素知之甚少。这 这对非裔美国人尤其重要，因为他们不成比例地患有哮喘并发症，并且可能对治疗反应不大。这项研究旨在量化非裔美国人和白色患者对ICS治疗的反应，并使用尖端遗传技术来寻找预测治疗反应的标记物。从这项研究中获得的知识可能有助于临床医生选择最有可能对患者有效的哮喘治疗方法，并为未来的哮喘治疗提供见解。

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.