LONG-TERM OXYGEN TREATMENT TRIAL (LOTT) PHARMACOGENOMICS ANCILLARY STUDY

长期氧气治疗试验 (LOTT) 药物基因组学辅助研究

基本信息

批准号：
8540454
负责人：
CRAIG P HERSH
金额：
$ 42.48万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2009-09-04 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8540454
关键词：
Address Ancillary Study Animals Antioxidants Candidate Disease Gene Cause of Death Characteristics Chronic Obstructive Airway Disease Clinical Clinical Trials Disease Disease susceptibility Exercise Exercise Tolerance Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Genome Genomics Genotype Hereditary Disease Heterogeneity Human Hypoxemia Individual Linkage Disequilibrium Medical Research Medicare Medicine Metabolism Molecular Profiling National Heart, Lung, and Blood Institute Oxidants Oxygen Oxygen Therapy Care Participant Pathway interactions Patients Pharmacogenetics Pharmacogenomics Physicians Public Health Quality of life RNA Randomized Sampling Single Nucleotide Polymorphism Susceptibility Gene Testing Toxic effect United States Variant base cohort cost follow-up genetic association genetic variant genome-wide genome-wide linkage improved mortality novel oxygen toxicity peripheral blood public health relevance response treatment trial

项目摘要

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and mortality from COPD continues to increase. Long-term oxygen therapy has been shown to reduce mortality in COPD patients with severe hypoxemia and is one of the only treatments for COPD with a proven survival benefit. The Long-term Oxygen Treatment Trial (LOTT) is an NHLBI-sponsored clinical trial to determine whether COPD patients with moderate hypoxemia will benefit from continuous oxygen therapy. Results of earlier studies in moderately hypoxemic COPD patients suggest heterogeneity in the response to oxygen. In other diseases, pharmacogenetic influences on oxygen toxicity and on oxygen benefit have been demonstrated. However, the impact of pharmacogenetics on the response to oxygen therapy in COPD is unknown. The overall hypothesis is that a set of oxygen-responsive genes will be differentially expressed in COPD patients treated with supplemental oxygen and that inter-individual variation in these oxygen-responsive genes will predict change in exercise tolerance and disease-specific quality of life (QoL) in COPD patients treated with long-term oxygen therapy. To test this hypothesis, we will address three Specific Aims: 1) Genomic profiling of response to oxygen therapy: We will collect peripheral blood for RNA at baseline (pre- randomization) and at follow-up, and perform whole-genome gene expression profiling in 100 LOTT participants randomized to supplemental oxygen to define a set of genes that are significantly up- or down- regulated in response to oxygen therapy. We will test whether gene expression profiles predict change in exercise capacity and disease-specific QoL in response to long-term oxygen therapy. 2) Pharmacogenetics of long-term oxygen therapy: We will genotype linkage-disequilibrium tagging single nucleotide polymorphisms (SNPs) in 40-50 differentially expressed oxygen-responsive genes in 800 subjects randomized to supplemental oxygen and test for association with change in exercise capacity and disease-specific QoL in COPD patients treated with long-term oxygen therapy. We will also test whether these SNPs are associated with gene expression of the differentially expressed oxygen-responsive genes. 3) Replication of pharmacogenetic associations: For 120 SNPs significantly associated with change in exercise capacity disease-specific QoL in the initial 800 subjects, we will genotype a separate set of 1200 LOTT subjects to replicate genetic associations for response to long-term oxygen therapy. Significance: This study will further our understanding of the effects of supplemental oxygen in COPD and may allow for better prediction of patients most likely to benefit or most likely to be harmed by long-term oxygen therapy. PUBLIC HEALTH RELEVANCE: The Long-term Oxygen Treatment Trial (LOTT) Pharmacogenomics Ancillary Study will improve our understanding of the effects of treating chronic obstructive pulmonary disease (COPD) patients with supplemental oxygen. The information gained may eventually allow physicians to predict which COPD patients are most likely to benefit or most likely to be harmed by long-term oxygen therapy.

描述（由申请人提供）：慢性阻塞性肺病 (COPD) 是美国第四大死因，并且 COPD 的死亡率持续增加。长期氧疗已被证明可以降低患有严重低氧血症的慢性阻塞性肺病患者的死亡率，并且是唯一经证明具有生存益处的慢性阻塞性肺病治疗方法之一。长期氧疗试验 (LOTT) 是一项由 NHLBI 赞助的临床试验，旨在确定患有中度低氧血症的 COPD 患者是否会从持续氧疗中受益。早期对中度低氧血症慢性阻塞性肺病患者的研究结果表明，对氧气的反应存在异质性。在其他疾病中，药物遗传学对氧毒性和氧益处的影响已得到证实。然而，药物遗传学对 COPD 氧疗反应的影响尚不清楚。总体假设是，一组氧反应基因在接受补充氧气治疗的 COPD 患者中会有差异表达，这些氧反应基因的个体间差异将预测运动耐量和疾病特异性生活质量 (QoL) 的变化。）接受长期氧疗的慢性阻塞性肺病（COPD）患者。为了检验这一假设，我们将实现三个具体目标： 1) 对氧疗反应的基因组分析：我们将在基线（预随机化）和随访时收集外周血的 RNA，并进行全基因组基因表达分析在 100 名 LOTT 参与者中随机接受补充氧气，以确定一组对氧疗反应显着上调或下调的基因。我们将测试基因表达谱是否可以预测运动能力和疾病特异性生活质量因长期氧疗而发生的变化。 2) 长期氧疗的药物遗传学：我们将对 800 名随机接受补充氧的受试者中 40-50 个差异表达的氧反应基因进行连锁不平衡标记单核苷酸多态性 (SNP) 基因分型，并测试与运动能力和氧疗变化的关联。接受长期氧疗的慢性阻塞性肺病患者的疾病特异性生活质量。我们还将测试这些 SNP 是否与差异表达的氧响应基因的基因表达相关。 3) 药物遗传学关联的复制：对于最初 800 名受试者中与运动能力疾病特异性 QoL 变化显着相关的 120 个 SNP，我们将对一组单独的 1200 名 LOTT 受试者进行基因分型，以复制对长期氧疗反应的遗传关联。意义：这项研究将进一步了解补充氧气对慢性阻塞性肺病的影响，并可能更好地预测长期氧疗最有可能受益或最有可能受到伤害的患者。公众健康相关性：长期氧气治疗试验 (LOTT) 药物基因组学辅助研究将提高我们对补充氧气治疗慢性阻塞性肺病 (COPD) 患者效果的了解。获得的信息最终可能使医生能够预测哪些慢性阻塞性肺病患者最有可能受益或最有可能因长期氧疗而受到伤害。