Project Summary/Abstract During the initial funding period, we applied aptamer-based proteomic analysis (SomaLogic) to investigate cardiometabolic disease among African Americans (AAs) in the Jackson Heart Study (JHS). In published studies, we identified novel biomarkers that are associated with the development of left ventricular hypertrophy, CHF and with CKD over a decade before the onset of clinical disease, including plasma proteins that are differentially associated with outcomes in individuals of predominantly African vs. European ancestry. We also described how whole genome sequence analysis of the plasma proteome in individuals with African ancestry increases our power to detect novel genetic determinants. In addition to identifying over 100 new locus-protein associations, the associations suggest new mechanisms of genetically mediated diseases linked to African ancestry. We identified a novel association between variants in APOL1 and the protein CKAP2, as well as an association between ATTR amyloidosis and RBP4 levels in community dwelling individuals without CHF. In unpublished work, we have also identified novel determinants of incident CHD, including Secreted Transmembrane Protein 1 (SECTM1), a poorly characterized protein with potential chemotactic activity for monocytes. In follow-up in silico analyses, SNPs associated with circulating SECTM1 levels are also associated with the monocyte percentage of white blood cells in large human databases. Further, our pilot experiments in mice demonstrate that short term administration of recombinant SECTM1a (mouse homologue) increases pro- atherogenic and inflammatory Ly6Chi circulating monocytes, as well as monocyte progenitors in the bone marrow. These data suggest that SECTM1 may be a novel regulator of monocyte biology that contributes to CHD. More broadly, we have shown that large-scale proteomic profiling in well-characterized populations can identify proteins and pathways that may be causal for adverse cardiometabolic conditions. In this renewal, we will first extend our discovery efforts of novel biomarkers of incident CHD and its risk factors using the recently expanded, highly specific Olink 3,000-plex platform (Aim 1), which includes >2100 proteins that have not been assayed in a large number of AAs. In Aim 2, fine mapping of protein-associated genetic variants, co-localization studies with established CHD-associated variants, and Mendelian Randomization experiments will be used to assess causality of protein-associated variants for CHD, CKD, and other cardiometabolic conditions. For both Aims 1 & 2, findings will be replicated in a multi-ethnic population (MESA), and extended through multi-omic analyses involving extensive metabolomic data available in both JHS and MESA. Putative causal variants that emerge from these analyses will be validated in model systems in Aim 3, with initial studies focusing on SECTM1’s atherogenic potential in mouse models. In addition to SECTM1, we antic...