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

描述(申请人提供)：慢性阻塞性肺疾病(COPD)是美国的第四大死亡原因，COPD的死亡率持续上升。长期氧疗已被证明可以降低COPD严重低氧血症患者的死亡率，是唯一被证明对生存有好处的COPD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，旨在确定中度低氧血症的COPD患者是否将从持续氧疗中受益。早期对中度缺氧性COPD患者的研究结果表明，对氧气的反应是不同的。在其他疾病中，药物遗传学对氧气毒性和氧气效益的影响已经被证明。然而，药物遗传学对COPD患者氧疗反应的影响尚不清楚。总体假设是，在接受补充氧气治疗的COPD患者中，一组氧反应基因将出现差异表达，这些氧反应基因的个体间差异将预测长期氧疗治疗的COPD患者的运动耐量和疾病特异性生活质量(QOL)的变化。为了验证这一假设，我们将解决三个具体目标：1)氧疗反应的基因组图谱：我们将在基线(随机前)和随访时收集外周血中的RNA，并对100名随机接受补充氧气的LOTT参与者进行全基因组基因表达谱分析，以确定一组在氧疗反应中显著上调或下调的基因。我们将测试基因表达谱是否可以预测长期氧疗后运动能力和疾病特有的生活质量的变化。2)长期氧疗的药物遗传学：我们将在800名随机接受补充氧疗的受试者中，对40-50个差异表达的氧反应基因中的连锁不平衡标记单核苷酸多态(SNPs)进行分型，并测试与长期氧疗治疗的COPD患者运动能力变化和疾病特异性生活质量的相关性。我们还将测试这些SNP是否与差异表达的氧反应基因的基因表达有关。3)药物遗传相关性的复制：在最初的800名受试者中，对于与运动能力和疾病相关的生活质量变化显著相关的120个SNP，我们将对另一组1200名LOTT受试者进行基因分型，以复制对长期氧疗的遗传相关性。意义：这项研究将进一步加深我们对补充氧气在慢性阻塞性肺疾病中的影响的理解，并可能允许更好地预测最有可能受益于或最有可能受到长期氧疗伤害的患者。 公共卫生相关性：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疾病(COPD)患者的疗效的理解。所获得的信息最终可能使医生预测哪些COPD患者最有可能从长期氧疗中受益或最有可能受到伤害。

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.