Abstract:
Rationale: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airway obstruction and accelerated lung function decline. Our understanding of systemic protein biomarkers associated with COPD remains incomplete. Objectives: To determine what proteins and pathways are associated with impaired pulmonary function in a diverse population. Methods: We studied 6,722 participants across six cohort studies with both aptamer-based proteomic and spirometry data (4,566 predominantly White participants in a discovery analysis and 2,156 African American cohort participants in a validation). In linear regression models, we examined protein associations with baseline forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC). In linear mixed effects models, we investigated the associations of baseline protein levels with rate of FEV1 decline (ml/yr) in 2,777 participants with up to 7 years of follow-up spirometry. Results: We identified 254 proteins associated with FEV1 in our discovery analyses, with 80 proteins validated in the Jackson Heart Study. Novel validated protein associations include kallistatin serine protease inhibitor, growth differentiation factor 2, and tumor necrosis factor-like weak inducer of apoptosis (discovery β = 0.0561, Q = 4.05 × 10-10; β = 0.0421, Q = 1.12 × 10-3; and β = 0.0358, Q = 1.67 × 10-3, respectively). In longitudinal analyses within cohorts with follow-up spirometry, we identified 15 proteins associated with FEV1 decline (Q < 0.05), including elafin leukocyte elastase inhibitor and mucin-associated TFF2 (trefoil factor 2; β = -4.3 ml/yr, Q = 0.049; β = -6.1 ml/yr, Q = 0.032, respectively). Pathways and processes highlighted by our study include aberrant extracellular matrix remodeling, enhanced innate immune response, dysregulation of angiogenesis, and coagulation. Conclusions: In this study, we identify and validate novel biomarkers and pathways associated with lung function traits in a racially diverse population. In addition, we identify novel protein markers associated with FEV1 decline. Several protein findings are supported by previously reported genetic signals, highlighting the plausibility of certain biologic pathways. These novel proteins might represent markers for risk stratification, as well as novel molecular targets for treatment of COPD.
摘要:
背景:慢性阻塞性肺疾病(COPD)是一种复杂的疾病,其特征是气道阻塞和肺功能加速下降。我们对与COPD相关的系统性蛋白质生物标志物的理解仍然不完整。
目的:确定哪些蛋白质和途径与不同人群的肺功能受损有关?
方法:我们在6项队列研究中研究了6,722名参与者,同时使用基于适体的蛋白质组学和肺活量测定数据(发现分析中的4,566名主要是白人参与者,验证中的2,156名非裔美国人队列参与者)。在线性回归模型中,我们检查了蛋白质与基线FEV1和FEV1/FVC的相关性.在线性混合效应模型中,我们调查了2,777名参与者的基线蛋白质水平与FEV1下降率(mL/年)的关联,随访长达7年的肺活量测定。
结果:我们在我们的发现分析中鉴定了254种与FEV1相关的蛋白质,其中80种在杰克逊心脏研究中得到验证。新的经过验证的蛋白质关联包括kallistatin丝氨酸蛋白酶抑制剂,生长分化因子2和肿瘤坏死因子样弱凋亡诱导剂(发现β=0.0561,Q=4.05×10-10,β=0.0421,Q=1.12×10-3,β=0.0358,Q=1.67×10-3,分别)。在随访肺活量测定队列的纵向分析中,我们鉴定了15种与FEV1下降相关的蛋白质(Q<0.05),包括elafin白细胞弹性蛋白酶抑制剂和粘蛋白相关三叶因子2(β=-4.3mL/年,Q=0.049;β=-6.1毫升/年,Q=0.032;分别)。我们的研究强调的途径和过程包括异常的细胞外基质重塑,增强先天免疫反应,血管生成和凝血的失调。
结论:在这项研究中,我们在种族多样性人群中鉴定并验证了与肺功能特征相关的新型生物标志物和通路.此外,我们鉴定了与FEV1下降相关的新型蛋白质标记。先前报道的基因信号支持了一些蛋白质发现,强调某些生物途径的合理性。这些新的蛋白质可能代表了内分型和风险分层的标记,以及治疗COPD的新分子靶点。