PHARMACOGENOMICS OF INHALED CORTICOSTEROID RESPONSIVENESS IN PATIENTS WITH ASTHMA

哮喘患者吸入皮质类固醇反应的药物基因组学

• 批准号: 7912178
• 负责人: Keoki Williams
• 金额: $ 40.16万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912178
• 关键词: Accident and Emergency department; Accounting; Address; Admixture; Adrenal Cortex Hormones; African; African American; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Beclomethasone; Breathing; Bronchodilator Agents; Budesonide; Cessation of life; Clinical; Clinical Data; Confidence Intervals; DNA; Data; Diagnosis; Disease Management; Environmental Risk Factor; Ethnic Origin; Event; Forced expiratory volume function; Future; Genetic; Genetic Polymorphism; Genetic Techniques; Glucocorticoids; Guidelines; Health Care Costs; Hospitalization; In Vitro; Individual; Institution; Knowledge; Lymphocyte; Maps; Measures; Newly Diagnosed; Oral; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacogenomics; Population; Population Study; Predisposition; Pulmonary Function Test/Forced Expiratory Volume 1; Race; Reporting; Research Design; Research Personnel; Resistance; Respiratory physiology; Risk; Route; Sampling; Schools; Severities; Steroids; Structure; Symptoms; T-Lymphocyte; Terbutaline; Therapeutic; Time; United States; Visit; Work; cohort; design; experience; fluticasone; gene interaction; genome wide association study; hazard; improved; insight; novel; patient population; prevent; public health relevance; pulmonary function; randomized placebo controlled trial; response; treatment response; treatment trial

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.

描述（由申请人提供）：吸入的皮质类固醇（ICS）被认为是用于治疗和控制持续性哮喘患者的一线治疗。吸入类固醇的使用与气道反应性降低有关，肺功能提高，症状减少和更少的加重。然而，研究表明，ICS反应的大量受试者间变异性只有33％至50％的患者在治疗后1秒（FEV1）的强迫呼气量得到了显着改善。据估计，皮质类固醇耐药是所有与哮喘相关的医疗保健成本的一半。因此，了解导致皮质类固醇耐药性的因素既临床又有经济上的重要性。与白人患者相比，特别是非裔美国人患者对皮质类固醇疗法的反应似乎较小。但是，目前尚不清楚这种差异是否来自遗传或环境因素，还是吸入类固醇反应性（即建议的治疗途径）中是否存在差异。这个问题尤其重要，因为非裔美国人患者因哮喘相关并发症而遭受不成比例的痛苦。迄今为止，已经进行了研究，研究了皮质类固醇反应的潜在机制，但是没有一个研究对吸入的皮质类固醇反应能力，也没有旨在识别种群级别的潜在原因遗传因素。因此，在此应用中，我们首先计划评估在吸入6周的抗甲酸磷酸二吡啶酸酯（BD）治疗后6周后，非裔美国人和白人哮喘患者之间吸入的皮质类固醇反应性的差异（即FEV1的改善）。其次，我们将寻求确定与BD治疗的该队列中ICS反应性相关的遗传基因座。我们队列的多样性是一个独特的优势，因为它使我们能够同时使用关联分析和混合图来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暴露和临床结果的能力，以评估同一组的药物基因组相互作用（即哮喘与哮喘相关的急诊室就诊，与哮喘相关的住院和口腔固醇爆发）。最后，我们将验证在单独的，较大的哮喘患者中观察到的对哮喘恶化的药物X基因相互作用。后一组也将来自我们筛选的哮喘人群，并将构成我们拥有DNA和临床数据（即历史ICS暴露措施和临床结果）的人。因此，在此应用中，我们计划确定一组与ICS反应性相关的遗传多态性，这些反应性既可以改善肺功能，也可以改变与加剧相关的临床结果的改变。公共卫生相关性：吸入的皮质类固醇（IC）被认为是持续性哮喘的一线治疗方法，但对影响对该疗法反应的遗传因素知之甚少。这就是 对于因哮喘并发症而遭受不成比例的非裔美国人患者而言，他们对治疗的反应可能较小。这项研究旨在量化非裔美国人和白人患者对ICS疗法的反应，并使用尖端的遗传技术来寻找预测治疗反应的标记。从这项研究中获得的知识可以帮助临床医生选择最有可能为患者工作的哮喘治疗，并为未来的哮喘治疗剂提供见解。