Systemic Markers of Lung Function and FEV(1) Decline across Diverse Cohorts

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 analyses and 2,156 African American cohort participants in a validation). In linear regression models, we examined protein associations with baseline FEV(1) and FEV(1)/FVC. In linear mixed effects models we investigated the associations of baseline protein levels with rate of FEV(1) decline (mL/year) in 2,777 participants with up to 7 years of follow-up spirometry. RESULTS: We identified 254 proteins associated with FEV(1) 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, 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 trefoil factor 2 (β=-4.3 mL/year, Q=0.049; β=-6.1 mL/year, 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. CONCLUSION: In this study, we identify and validate novel biomarkers and pathways associated with lung function traits in a racially diverse population. Additionally, 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 endophenotyping and risk stratification, as well novel molecular targets for treatment of COPD.

• Ngo, D.
• Pratte, K. A.
• Flexeder, C.
• Petersen, H.
• Dang, H.
• Ma, Y.
• Keyes, M. J.
• Gao, Y.
• Deng, S.
• Peterson, B. D.
• Farrell, L. A.
• Bhambhani, V. M.
• Palacios, C.
• Quadir, J.
• Gillenwater, L.
• Xu, H.
• Emson, C.
• Gieger, C.
• Suhre, K.
• Graumann, J.
• Jain, D.
• Conomos, M. P.
• Tracy, R. P.
• Guo, X.
• Liu, Y.
• Johnson, W. C.
• Cornell, E.
• Durda, P.
• Taylor, K. D.
• Papanicolaou, G. J.
• Rich, S. S.
• Rotter, J. I.
• Rennard, S. I.
• Curtis, J. L.
• Woodruff, P.
• Comellas, A. P.
• Silverman, E. K.
• Crapo, J. D.
• Larson, M. G.
• Vasan, R. S.
• Wang, T. J.
• Correa, A.
• Sims, M.
• Wilson, J. G.
• Gerszten, R. E.
• O'Connor, G. T.
• Barr, R. G.
• Couper, D.
• Dupuis, J.
• Manichaikul, A.
• O'Neal, W.
• Tesfaigzi, Y.
• Schulz, H.
• Bowler, R.