Abstract
Integration of electronic health records with systems-level biomolecular data has led to the discovery that GlycA, a complex nuclear magnetic resonance (NMR) spectroscopy biomarker, predicts long-term risk of disease onset and death from myriad causes. To fine-map the molecular underpinnings of the disease risk of the heterogeneous GlycA signal, we used machine learning to build imputation models for GlycA’s constituent glycoproteins, then estimated glycoprotein levels in 11,861 adults across two population-based cohorts with long-term follow-up. While alpha-1-acid glycoprotein had the strongest correlation with GlycA, our analysis revealed that alpha-1 antitrypsin (AAT) was the most predictive of morbidity and mortality for the widest range of diseases, including heart failure (HR=1.60 per s.d., P=1×10−10), influenza and pneumonia (HR=1.37, P=6×10−10), and liver diseases (HR=1.81, P=1×10−6). Despite AAT’s well characterised role in suppressing inflammation, transcriptional analyses revealed elevated expression of diverse inflammatory immune pathways with elevated AAT levels, suggesting inadequate control of systemic inflammation. This study clarifies the molecular underpinnings of the GlycA biomarker and its associated disease risk, and indicates a previously unrecognised association between elevated AAT and severe disease onset and mortality.