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

ObjectiveDiabetes mellitus (DM) approximately doubles the risk of atherosclerotic cardiovascular disease (ASCVD) events, but the molecular basis is poorly understood. We aimed to define arterial differentially expressed genes (DEGs) associated with DM, validate hits as plasma proteins, and ascertain whether these complement ASCVD risk prediction tools. Research design and methodsRNA-sequencing data from the Genotype-Tissue Expression (GTEx) cohort was used to define DEGs associated with DM in two arterial sites in >90 people with DM and >330 controls. UK Biobank (UKB) was used to corroborate that DEGs in their plasma protein form were differentially abundant in people with DM and associated with ASCVD events. Finally, we assessed if including these plasma proteins improved performance of the SCORE2 and SCORE2-Diabetes ASCVD risk models. Results619 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 demonstrated associations with a range of incident ASCVD events. Addition of the 4 proteins to SCORE2 and SCORE2-Diabetes (for people without and with DM, respectively) improved the population-level discrimination, classification and calibration of these models. ConclusionsDM is associated with a distinct arterial gene expression profile, hits from which are associated with ASCVD events and add value to risk prediction. Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/26345847v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@19e0228org.highwire.dtl.DTLVardef@9fd086org.highwire.dtl.DTLVardef@3315f0org.highwire.dtl.DTLVardef@1e5770f_HPS_FORMAT_FIGEXP M_FIG C_FIG