Abstract Body: Introduction
Pulmonary function decline is linked to an increased cardiovascular disease risk, but the underlying mechanisms remain unclear.

Hypothesis
We hypothesize that protein biomarkers are associated with pulmonary function decline and subsequent incident chronic obstructive pulmonary disease (COPD), coronary heart disease (CHD), heart failure (HF), and all-cause mortality.

Methods
Spirometric measurements of forced expiratory volume in one second (FEV1) were collected at visits 2 (1990–92) and 5 (2011–13) in the Atherosclerosis Risk in Communities (ARIC) Study for discovery, and at years 6 (1993–94) and 9 (1995–96) in the Cardiovascular Health Study (CHS) for replication. Proteomic data were measured using the 5k SOMAscan platform. Annualized FEV1 decline was analyzed using linear regression models among COPD-free participants at baseline, who had complete data for FEV1, proteomics, and covariates at both time points in each study. Proteins associated with FEV1 decline were further analyzed with incident COPD using logistic regression, and with incident CHD, HF, and mortality across the entire cohort using Cox proportional hazards models, adjusting for age, sex, race, smoking status, body mass index, lipids, kidney function and comorbidity status.

Results
Among the 4,766 proteins evaluated, 24 were significantly associated with annualized FEV1 decline (FDR<0.05) in ARIC (N=3,435; baseline mean age: 54 years; 18% Black; 58% female). Of these metabolites, seven were associated with incident COPD, 11 with CHD, 20 with HF, and 21 with all-cause mortality (FDR<0.05, Figure 1). Three proteins, biotinidase, OMGP, and CA2D3, were inversely associated with all four outcomes (Figure 2). Out of 24 identified proteins in ARIC, seven displayed consistent directional effects with FEV1 decline in CHS (N=1,848; baseline mean age: 74 years; 15% Black; 60% female). In addition, SLIK5 (OR=0.78, 95% CI=0.68-0.90) and CA2D3 (OR=0.80, 95% CI=0.69-0.92) were associated with a lower risk of COPD in ARIC, over 22-year follow-up (382 events). These associations were replicated in CHS (67 events), where SLIK5 (OR=0.73, 95% CI=0.53-0.99) and CA2D3 (OR=0.73, 95% CI=0.56-0.96) were both associated with lower COPD incidence over 3-year follow-up.

Conclusions
We identified circulating proteins associated with pulmonary function decline and subsequent cardiovascular outcomes, providing insights into the molecular mechanism of pulmonary function and incident cardiovascular disease.