Systemic Biomarkers of Lung Function and FEV <sub>1</sub> Decline Across Multiple Cohorts

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is a common, complex respiratory disease characterized by airway obstruction and accelerated lung function decline. Our understanding of systemic protein biomarkers associated with COPD remains incomplete. We tested whether aptamer-based protein profiling could identify markers and pathways related to impaired pulmonary function and lung function decline in multiple studies. Methods: We studied 3,827 non-Hispanic/European White participants across six cohort studies with both aptamer-based proteomic and spirometry data. In linear regression models we examined protein associations with baseline FEV1 and FEV1/FVC. In linear mixed effects models we investigated the associations of baseline protein levels with rate of FEV1 decline (mL/year) in 2,636 participants with up to 7 years of follow-up spirometry. Findings: We identified 198 proteins associated with FEV1, twelve of the proteins were also significantly associated with FEV1/FVC, including retinal binding protein 4 FEV1 : β=0·0307, Q= 2·18×10-4; FEV1/FVC: β=0·008, Q =4·0×10-3 ) and bactericidal permeability-increasing protein (FEV1 : β=-0·0280, Q =6·80×10-3; FEV1/FVC: β=0·0050, Q =0·04). We further identified 15 proteins associated with the rate of FEV1 decline ( Q <0·05), including coagulation-related tissue factor and basement membrane-associated nidogen (β=-5·21 mL/year, Q =0·016 and β=-4·90 mL/year, Q =0·020, respectively). Pathways and processes associated with lung function included extracellular matrix organization, coagulation, and angiogenesis. Interpretation: In this study, we identified novel biomarkers and pathways associated with lung function and lung function decline. Additionally, several protein findings support previously reported genetic signals, highlighting the plausibility of certain biologic pathways. These novel proteins might represent disease markers of at-risk individuals and/or novel molecular targets with the potential to modify COPD clinical course. Funding Statement: COPDGene Phase 3: Grant Support and Disclaimer: The project described was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the National Heart, Lung, and Blood Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health; COPD Foundation Funding: The COPDGene® project is also supported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, and Sunovion; FHS: This work was supported by R01HL132320 and R01HL133870. The Framingham Heart Study (FHS) acknowledges the support of contracts NO1-HC25195, HHSN268201500001I and 75N92019D00031. KORA: The KORA study was initiated and financed by the Helmholtz Zentrum Munchen – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, as part of LMUinnovativ. This work was also supported by the Comprehensive Pneumology Center Munich (CPC-M) as member of the German Center for Lung Research (DZL). LSC: This work was supported by funding from the State of New Mexico. MESA-TOPMed/MESA Lung Support: Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI), with core services provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I) and the TOPMed Data Coordinating Center (3R01HL120393-2S1; contract HHSN268201800001I). Proteomics data for the MultiEthnic Study of Atherosclerosis MESA; phs001416) were generated through the TOPMed MESA Multi-Omics project (HHSN2682015000031/HHSN26800004). The MESA Lung Study is supported by R01-HL077612 and R01-HL093081. SPIROMICS. This work was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C), grants from the NIH/NHLBI (U01 HL137880 and U24 HL141762), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; BoehringerIngelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan. Declaration of Interests: None. Ethics Approval Statement: The respective local Institutional Review Boards approved all study protocols and informed consent was obtained from all participants.