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

基本信息

批准号：
8435330
负责人：
Keoki Williams
金额：
$ 66.89万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8435330
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 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 cell response Terbutaline Therapeutic Time United States Visit Work cohort design disorder control experience fluticasone gene interaction genome wide association study hazard improved insight novel patient population prevent pulmonary function randomized placebo controlled trial response treatment response treatment trial

项目摘要

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.

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疗法。使用吸入类固醇可降低气道反应性、改善肺功能、减轻症状和减少病情加重。然而，研究表明 ICS 反应存在相当大的受试者间差异，只有 33% 至 50% 的患者在治疗后 1 秒用力呼气量 (FEV1) 出现显着改善。据估计，皮质类固醇耐药性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抵抗的因素具有临床和经济上的重要意义。尤其是非洲裔美国患者，与白人患者相比，似乎对皮质类固醇治疗的反应较小。然而，目前尚不清楚这种差异是否是由遗传或环境因素造成的，或者吸入类固醇反应性（即推荐的治疗途径）是否存在差异。这个问题特别重要，因为非裔美国患者遭受哮喘相关并发症的比例不成比例。迄今为止，已有研究探讨皮质类固醇反应性的潜在机制，但没有一项研究涉及吸入皮质类固醇反应性，这些研究也不是旨在识别人群水平上潜在的致病遗传因素。因此，在本申请中，我们首先计划评估非裔美国人和白人哮喘患者在吸入二丙酸倍氯米松 (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，我们将寻求在接受 BD 治疗 6 周的队列中寻找与 ICS 反应性相关的遗传位点。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图谱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群体中纵向评估 ICS 暴露和临床结果的能力，以评估药物基因组学相互作用对哮喘恶化的影响（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））在同一组中。最后，我们将在一个更大的单独的哮喘患者队列中验证观察到的药物与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，在本申请中，我们计划鉴定一组与 ICS 反应性相关的遗传多态性，ICS 反应性的定义是肺功能的改善和恶化相关临床结果的改变。