Depression and functional outcomes in COPD: Impact of genetics and inflammation

描述（由申请人提供）：抑郁症在慢性阻塞性肺疾病（COPD）患者中非常普遍，并与不良临床结局相关。该提案的总体目标是检查炎症和遗传危险因素对重度COPD患者抑郁的影响，并评估炎症，遗传和抑郁对功能结局变化的综合影响。越来越多的证据表明，COPD与影响其他器官系统的全身性炎症有关。高水平的全身炎症标志物也与健康和慢性病人群中抑郁症的风险增加有关。参与情感障碍病理生理学的神经递质5-羟色胺由5-羟色胺转运体（SERT）调节，所述5-羟色胺转运体控制5-羟色胺在脑突触处的再摄取。最近的研究报告表明，SERT多态性与抑郁症有关，这表明该基因的变体可能在确定COPD患者是否会在疾病过程中发生抑郁症方面很重要。SERT多态性与抑郁症相关的初步数据以及表明炎症、抑郁症和COPD之间关系的数据强烈支持进行大规模前瞻性研究来严格检验这些关系。因此，本前瞻性研究的目的是：1）检查SERT多态性与抑郁症之间的关系; 2）检查全身炎症标志物之间的双向纵向关系（CRP、IL-6和TNF-1）与COPD患者抑郁症状的关系，并探讨COPD急性加重和SERT基因型在这种关系中的作用;和3）确定2年内抑郁、炎症和SERT基因型对COPD患者功能结果（6分钟步行测试距离、用加速度计测量的体力活动、呼吸困难严重程度和健康相关生活质量）下降的影响。将在30个月内从两个临床研究中心招募COPD GOLD II-IV期患者（n=350）。基线、第1年和第2年的评估将包括：用于基因分型（5-HTTLPR和STin 2 VNTR）和细胞因子测定的血液样本、肺活量测定、抑郁症评估、功能能力（6分钟步行试验）、体能（来自加速度计的体力活动）、呼吸困难和健康相关生活质量（HRQL）。我们将使用先进的纵向统计技术，结构方程建模和潜在增长模型，以评估抑郁，炎症和功能状态的变化动态，这些过程随着时间的推移而展开。公共卫生相关性：预计到2020年，COPD将成为第三大死亡原因。了解遗传学和炎症对抑郁症的影响以及这些因素对功能结局下降的相对影响，将有助于开发更有针对性的医疗和行为干预措施，以改善COPD患者的抑郁症和功能结局。 公共卫生相关性：慢性阻塞性肺疾病（COPD）是美国第四大死亡原因，其特征在于慢性、进行性恶化的呼吸短促、咳嗽和痰产生，并且25- 50%的患者将发展成抑郁症状。该提案的总体目标是检查炎症和遗传危险因素对中重度COPD患者抑郁的影响，并评估炎症、遗传和抑郁对功能结局变化的综合影响。了解这些关系将有助于制定更有针对性的医疗和行为干预措施，以改善COPD患者的抑郁和功能结局。

DESCRIPTION (provided by applicant): Depression is highly prevalent among patients with chronic obstructive pulmonary disease (COPD) and is associated with adverse clinical outcomes. The overall goal of this proposal is to examine the impact of inflammation and genetic risk factors on depression in patients with severe COPD, and to assess the combined effects of inflammation, genetics, and depression on changes in functional outcomes. There is increasing evidence that COPD is associated with systemic inflammation that impacts other organ systems. High levels of systemic inflammatory markers have also been linked to increased risk of depression in both healthy and chronically ill populations. The neurotransmitter serotonin which is involved in the pathophysiology of affective disorders is regulated by the serotonin transporter (SERT) that controls reuptake of serotonin at brain synapses. Recent studies report that SERT polymorphisms are associated with depression, suggesting that variants of this gene may be important in determining whether patients with COPD will develop depression during the course of their disease. The preliminary data linking SERT polymorphisms with depression and data suggesting a relationship between inflammation, depression and COPD strongly argue for a large scale prospective study to critically test these relationships. Therefore, the aims of this prospective study of patients with moderate to very severe COPD are to: 1) Examine the relationship between SERT polymorphisms with depression; 2) Examine the bi-directional longitudinal relationship between markers of systemic inflammation (CRP, IL-6, and TNF-1) and depressive symptoms in COPD, and explore the role of exacerbations and SERT genotype in this relationship; and 3) Determine the effect of depression, inflammation, and SERT genotype on decline in functional outcomes (six minute walk test distance, physical activity measured with accelerometers, dyspnea severity, and health related quality of life) in COPD over 2 years. Patients with COPD GOLD Stages II-IV (n=350) will be recruited from two clinical sites over 30 months. Assessments at baseline, year 1 and year 2 will include: blood samples for genotyping (5-HTTLPR and STin2 VNTR) and cytokine assays, spirometry, assessment of depression, functional capacity (six minute walk test), performance (physical activity derived from accelerometry), dyspnea, and health related quality of life (HRQL). We will use advanced longitudinal statistical techniques, structural equations modeling and latent growth models, to assess the dynamics of change in depression, inflammation, and functional status as posited by our models as these processes unfold over time. Public Health Relevance: COPD is expected to be the third leading cause of death by 2020. Understanding the impact of genetics and inflammation on depression as well as the relative influence of these factors on the decline in functional outcomes will inform the development of more tailored medical and behavioral interventions to improve depression and functional outcomes in patients with COPD. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of death in the United States, is characterized by chronic, progressive worsening shortness-of-breath, cough and sputum production, and 25- 50% of patients will develop depressive symptoms. The overall goal of this proposal is to examine the impact of inflammation and genetic risk factors on depression in patients with moderate to severe COPD, and to assess the combined effects of inflammation, genetics, and depression on changes in functional outcomes. Understanding these relationships will in inform the development of more tailored medical and behavioral interventions to improve depression and functional outcomes in patients with COPD.