Analysis of the diabetic arterial transcriptome to define novel biomarkers of macrovascular disease

Diabetes mellitus (DM) approximately doubles the risk of atherosclerotic cardiovascular disease (ASCVD) events, but the molecular basis is poorly understood. Using RNA-sequencing data from two arterial sites in >90 people with DM and >330 controls, we defined differentially expressed genes (DEGs) associated with DM. UK Biobank (UKB) was then used to corroborate that DEGs in their plasma protein form were differentially abundant in people with DM and associated with ASCVD events. 619 and 356 DEGs were associated with DM in the thoracic aorta and tibial artery, respectively. Of these, 22 were common to both arteries, all of which were directionally concordant. Of these, 5 were included in the UKB plasma proteomics dataset and we corroborated 4 (ACP5, LEFTY2, LILRA5 and PSME2) as showing concordant differential abundance in people with DM; all were associated with a range of incident ASCVD events. Addition of the 4 proteins to the SCORE2 and SCORE2-Diabetes risk models (for people without and with DM, respectively) improved the population-level discrimination, classification and calibration of these models. These data show that DM is associated with a distinct arterial gene expression profile, hits from which are associated with ASCVD events and add value to risk prediction.