Cardiometabolic diseases, such as type 2 diabetes and cardiovascular disease, have a high public health burden. Understanding the genetically-determined regulation of proteins that are dysregulated in disease can help to dissect the complex biology underpinning them. Here, we perform a protein quantitative trait locus (pQTL) analysis of 255 serum proteins relevant to cardiometabolic processes in 2893 individuals. Meta-analysing whole-genome sequencing (WGS) data from two Greek cohorts, MANOLIS (n = 1356; 22.5x WGS) and Pomak (n = 1537; 18.4x WGS), we detect 302 independently-associated pQTL variants for 171 proteins, including 12 rare variants (minor allele frequency [MAF] < 1%). We additionally find 15 pQTL variants that are rare in non-Finnish European populations, but have drifted up in frequency in the discovery cohorts here. We identify proteins causally associated with cardiometabolic traits, including MEP1B for high-density lipoprotein levels; and describe a knock-out Mep1b mouse model. Our findings furnish insights into the genetic architecture of the serum proteome, identify new protein-disease relationships, and demonstrate the importance of isolated populations in pQTL analysis.