Proteogenomic Analysis of Coronary Artery Calcification in Human Populations.

Joint use of multiple molecular layers can be useful to prioritize targets for mechanistic studies. Application of this approach to coronary disease in large populations is an emerging field. We used reported circulating proteomic data (Somascan aptamer-based) from ≈3000 individuals in the CARDIA study (Coronary Artery Risk Development in Young Adults), measuring association with prevalent and 10-year incident coronary artery calcium (CAC) score. We used a multiparametric approach to prioritize circulating protein-CAC associations via genomics of circulating protein levels and coronary artery transcription. Proteins linked to prevalent/incident CAC in CARDIA implicated pathogenic mechanisms of vascular disease, including fibrosis and inflammation (GDF-15 [growth/differentiation factor 15], CDCP1 [CUB domain-containing protein 1], GSN [gelsolin], THBS2 [thrombospondin-2], chemokines, RNAS6 [ribonuclease K6]), oxidative lipid metabolism (CILP2; cartilage intermediate layer protein 2), extracellular matrix remodeling and signaling (MMPs [matrix metalloproteinases], TIMP-1 [tissue inhibitor of metalloproteinases 1], integrins), calcification (Notch 1, ARHGAP36 [Rho GTPase-activating protein 36]), and metabolism (GIP [gastric inhibitory polypeptide]), as well as new proteins not previously reported. Using proteome-wide association study genetic approaches, several targets with nominal evidence in CAC proteomics were associated with atherosclerosis or myocardial infarction in over 300K individuals, including PCSK9 (proprotein convertase subtilisin/kexin type 9) and APOC1. Finally, the coronary artery-specific transcriptome-wide association study of CAC yielded genes with previously implicated mechanistic roles in vascular homeostasis, inflammation, and metabolism, as well as genes without previously described function in CAC. Overlap across CAC proteomics and transcriptome-wide association study highlighted genes involved in vascular inflammation (S100A9), cardiac development (HES1 [transcription factor HES-1]), vessel wall structure (SPARCL1 [SPARC-like protein 1]), and vascular dysfunction or plaque (NOTCH3 [neurogenic locus notch homolog protein 3], TNFSF12 [tumor necrosis factor ligand superfamily member 12], S100A12 [protein S100-A12]). These results report population-level multiomics in human coronary calcification, presenting a method to identify disease-relevant targets through integration of human genetic approaches with multiomics.