GlycA as an Effect Modifier of Protein-Mortality Associations: A Prospective Cohort Study

The heterogeneity in health effects of circulating proteins remained unclear. Previous studies have identified that glycoprotein acetyls (GlycA), a stable biomarker of inflammation, were associated with risks of mortality and chronic diseases. However, it remained unclear whether the health risks of proteins may differ across people with varied GlycA levels. Based on the multi-omics profiling of the UK Biobank prospective cohort, we evaluated whether GlycA statistically modifies the protein-mortality associations. In the discovery dataset (n = 24,134), we observed that GlycA significantly modified the associations of ANG, CRHBP, CXCL16, and PRRT3 with all-cause mortality, and these findings were replicated in the validation dataset (n = 6081). Subgroup analyses further indicated that associations between these proteins and mortality can be modulated by GlycA levels. Through exploratory analyses focused on chronic diseases and cause-specific mortality, we identified that cross-products of GlycA with these proteins can be associated with cancer mortality and heart failure. Together, the findings will expand our understanding of heterogeneity in protein-health associations and highlight several potential therapeutic targets for interventions across people with varied inflammation status.