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

描述(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，并与不良的临床结果相关。这项建议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果变化的综合影响。越来越多的证据表明，COPD与影响其他器官系统的全身炎症有关。在健康和慢性病人群中，高水平的全身炎症标志物也与抑郁症风险的增加有关。参与情感性精神障碍病理生理学的神经递质5-羟色胺受5-羟色胺转运体(SERT)的调节，SERT控制5-羟色胺在脑突触的重新摄取。最近的研究报道，SERT基因多态性与抑郁症相关，这表明该基因的变异可能在确定COPD患者在疾病过程中是否会发展为抑郁症方面发挥重要作用。将SERT基因多态性与抑郁症联系起来的初步数据，以及表明炎症、抑郁症和COPD之间关系的数据，强烈主张进行大规模前瞻性研究，对这些关系进行批判性测试。因此，这项针对中重度COPD患者的前瞻性研究的目的是：1)检测SERT基因多态性与抑郁的关系；2)检测全身炎症标志物(CRP、IL-6和TNF-1)与COPD抑郁症状之间的双向纵向关系，并探讨病情加重和SERT基因在这种关系中的作用；3)确定抑郁、炎症和SERT基因对2年以上COPD患者功能结果(6分钟步行距离、加速计测量的体力活动、呼吸困难严重程度和健康相关生活质量)下降的影响。COPD GOLD期II-IV期(n=350)的患者将在30个月内从两个临床地点招募。基线、第一年和第二年的评估将包括：用于基因分型(5-HTTLPR和STin2 VNTR)和细胞因子分析的血液样本、肺活量测定、抑郁症评估、功能能力(六分钟步行试验)、表现(来自加速计量学的体力活动)、呼吸困难和与健康相关的生活质量(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，来评估随着时间的推移，我们的模型所假定的抑郁、炎症和功能状态的变化动态。

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.