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，COPD的死亡率持续增加。长期氧疗已被证明可降低伴有严重低氧血症的COPD患者的死亡率，并且是唯一一种经证实具有生存获益的COPD治疗方法。长期氧疗试验（LOTT）是一项由NHLBI申办的临床试验，旨在确定中度低氧血症的COPD患者是否会从持续氧疗中获益。早期在中度低氧血症COPD患者中的研究结果表明，对氧的反应存在异质性。在其他疾病中，已证实药物遗传学对氧毒性和氧益处的影响。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，一组氧响应基因将在接受补充氧气治疗的COPD患者中差异表达，并且这些氧响应基因的个体间差异将预测接受长期氧气治疗的COPD患者的运动耐量和疾病特异性生活质量（QoL）的变化。为了检验这一假设，我们将提出三个具体目的：1）对氧疗法的响应的基因组分析：我们将在基线（随机化前）和随访时收集外周血的RNA，并在100名随机接受补充氧的LOTT参与者中进行全基因组基因表达分析，以定义一组响应于氧疗法而显著上调或下调的基因。我们将测试基因表达谱是否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：我们将对800名随机接受补充氧治疗的受试者的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，并检测长期氧疗治疗的COPD患者运动能力和疾病特异性QoL变化的相关性。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例受试者中与运动能力疾病特异性QoL变化显著相关的120个SNP，我们将对1200例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。重要性：这项研究将进一步了解COPD患者辅助供氧的效果，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。 公共卫生相关性：长期氧疗试验（LOTT）药物基因组学辅助研究将提高我们对慢性阻塞性肺疾病（COPD）患者辅助供氧治疗效果的理解。所获得的信息最终可能使医生能够预测哪些COPD患者最有可能从长期氧气治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.