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

Debby Ngo, Katherine A. Pratte, Claudia Flexeder, Hans Petersen, Hong Dang, Yanlin Ma, Michelle J. Keyes, Yan Gao, Shuliang Deng, Bennet D. Peterson, Laurie A. Farrell, Victoria M. Bhambhani, Cesar Palacios, Juweria Quadir, Lucas Gillenwater, Hanfei Xu, Claire Emson, Christian Gieger, Karsten Suhre, Johannes GraumannDeepti Jain, Matthew P. Conomos, Russell P. Tracy, Xiuqing Guo, Yongmei Liu, W. Craig Johnson, Elaine Cornell, Peter Durda, Kent D. Taylor, George J. Papanicolaou, Stephen S. Rich, Jerome I. Rotter, Steven I. Rennard, Jeffrey L. Curtis, Prescott G. Woodruff, Alejandro P. Comellas, Edwin K. Silverman, James D. Crapo, Martin G. Larson, Ramachandran S. Vasan, Thomas J. Wang, Adolfo Correa, Mario Sims, James G. Wilson, Robert E. Gerszten, George T. O’Connor, R. Graham Barr, David Couper, Josée Dupuis, Ani Manichaikul, Wanda K. O’Neal, Yohannes Tesfaigzi, Holger Schulz, Russell P. Bowler

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 b = 0.0561, Q = 4.05 3 10210; b = 0.0421, Q = 1.12 3 1023; and b = 0.0358, Q = 1.67 3 1023, 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; b = 24.3 ml/yr, Q = 0.049; b = 26.1 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.

Original languageEnglish (US)
Pages (from-to)1124-1135
Number of pages12
JournalAnnals of the American Thoracic Society
Volume20
Issue number8
DOIs
StatePublished - Aug 2023
Externally publishedYes

Keywords

  • airflow obstruction
  • biomarkers
  • proteomics

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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