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

描述（由申请人提供）：慢性阻塞性肺疾病（COPD）是美国第四大死亡原因，并且COPD的死亡率持续增加。长期氧疗已被证明可降低严重低氧血症COPD患者的死亡率，并且是COPD治疗中唯一被证明具有生存益处的治疗方法之一。长期氧疗试验（LOTT）是nhlbi赞助的一项临床试验，旨在确定中度低氧血症COPD患者是否会从持续氧疗中受益。早期对中度低氧性COPD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，已证实药物遗传对氧毒性和氧益处的影响。然而，药物遗传学对COPD患者氧疗应答的影响尚不清楚。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长期氧治疗的COPD患者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)对氧治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RNA，并在100名随机分配到补充氧组的LOTT参与者中进行全基因组基因表达分析，以确定一组在氧治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能预测长期氧疗后运动能力和疾病特异性生活质量的变化。2)长期氧疗的药物遗传学：我们将在800名随机接受补充氧治疗的受试者中，对40-50个差异表达的氧反应基因的连锁不平衡标记单核苷酸多态性（snp）进行基因分型，并检测其与长期氧疗COPD患者运动能力和疾病特异性生活质量变化的关系。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生活质量变化显著相关的120个snp，我们将对1200名LOTT受试者进行单独的基因分型，以复制对长期氧疗反应的遗传关联。意义：本研究将进一步加深我们对慢性阻塞性肺病补充氧的作用的理解，并可能允许更好地预测患者最可能受益或最可能受到长期氧治疗的伤害。

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.