Systemic Markers of Lung Function and Forced Expiratory Volume in 1 Second Decline across Diverse Cohorts

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.

Keywords: airflow obstruction; biomarkers; proteomics.

Figure 1.

Flow chart of the proteomic analysis plan. COPD = chronic obstructive pulmonary disease; FEV₁ = forced expiratory volume in 1 second; FHS = Framingham Heart Study; FVC = forced vital capacity; JHS = Jackson Heart Study; KORA = Kooperative Gesundheitsforschung in der Region Augsburg (Southern Germany); LSC = Lovelace Smokers Cohort; MESA = Multi-Ethnic Study of Atherosclerosis; SPIROMICS = Subpopulations and Intermediate Outcome Measures in COPD Study.

Figure 2.

Protein associations with baseline forced expiratory volume in 1 second (FEV₁). Volcano plot showing multivariable-adjusted protein associations with FEV₁. All colored circles above the −log₁₀ Q = 0.05 line represent proteins with significant associations with FEV₁ in discovery cohort meta-analyses. Red circles highlight proteins associated with FEV₁ in both discovery and Jackson Heart Study validation analysis (Q < 0.05, accounting for testing associations in 254 significant proteins found in discovery). See Table E2 for details for all significant protein associations with FEV₁ in discovery and validation analyses. Cohort level results for all proteins and all traits in discovery and validation are shown in Table E3. Annotation of protein full name, UniProt, EntrezGene, and aptamer sequence IDs are included across all supplementary tables. BMPR1A = bone morphogenetic receptor type 1A; RBP = retinol binding protein; RGM = repulsive guidance molecule.

Figure 3.

Proteins associated with both (A) forced expiratory volume in 1 second (FEV₁) and (B) FEV₁/forced vital capacity (FVC). Proteins associated with both FEV₁ and FEV₁/FVC in discovery cohort meta-analyses (Q < 0.05). Proteins are listed in order of ascending β estimate for FEV₁ association. See Tables E2 and E5 for details for all significant protein associations with FEV₁ and FEV₁/FVC in discovery and validation analyses, respectively. Cohort-level results are shown in Table E3. *Proteins associated with both FEV₁ and FEV₁/FVC in Jackson Heart Study validation analyses (Q < 0.05). BMPR-1A = bone morphogenetic receptor type 1A; CI = confidence interval; LBP = lipopolysaccharide binding protein; RBP = retinol binding protein; RGM = repulsive guidance molecule.

Figure 4.

Proteins associated with rate of forced expiratory volume in 1 second (FEV₁) decline. Meta-analyses of linear mixed-effects models for FHS (Framingham Heart Study), KORA (Kooperative Gesundheitsforschung in der Region Augsburg [Southern Germany]), COPDGene, and LSC (Lovelace Smokers Cohort); Q < 0.05. Proteins listed in order of ascending β estimate for FEV₁ decline association. Models were adjusted for age, sex, height, smoking status and pack-years, and assay plate and batch (if applicable). Sample size varied because some proteins were not measured in SomaScan Version 1.1k for FHS batch 1 and KORA. β estimates >0 indicate higher levels of protein associated with slower rate of decline and <0 indicate higher levels of proteins associated with faster rate of decline. See Table E6 for details for all significant protein associations with FEV₁ decline, including annotation for protein full name, UniProt, EntrezGene, and aptamer sequence IDs. Cohort level results are shown in Table E3. FSH = follicular stimulating hormone; IL1RL1 = interleukin-1 receptor-like 1; LH = luteinizing hormone; REG4 = regenerating islet-derived protein 4; SLPI = secretory leukocyte protease inhibitor; TF = tissue factor; TFF2 = trefoil factor 2.