Plasma proteins are integral to gene-regulatory networks acting within and across blood cells, the arterial wall and major metabolic organs

The plasma proteome is the future for diagnostic markers for common diseases, like cardiometabolic disorders (CMDs) and coronary artery disease (CAD). The reliability of these markers requires identifying their source-organ(s). We profiled 974 plasma proteins in 532 CAD-patients of the STARNET study with arterial wall, major metabolic organ, and blood transcriptomic data. 144 plasma cis-pQTLs colocalized with tissue eQTLs including eight CMD/CAD GWAS genes. 262 plasma proteins correlated with their corresponding tissue “seed” genes whereof 101 in the liver. 851 plasma proteins were strongly associated with the activity of gene-regulatory networks (GRNs), particularly cross-tissue GRNs. The Adipose-Liver Plasma LeptIN-regulating GRN78 with the top key driver UCHL1 in fat stood out. Beyond genetics, explaining up to 20% of plasma protein variation, and a limited number of mostly hepatic seed genes, plasma proteins are integral to GRNs acting within and across blood cells, the arterial wall and major metabolic organs.