PROJECT SUMMARY Human genetic investigations have nominated hundreds of novel genomic loci harboring genes that influence a range of cardiovascular (CV) diseases and their risk factors, including plasma lipids. However, only a fraction of these novel loci have been investigated to determine the causal genes and underlying molecular mechanisms leading to increased risk of—or protection from—CV disease. While LDL reduction is effective in reducing risk of atherosclerotic cardiovascular disease, other common cardiovascular diseases such as peripheral arterial disease, abdominal aortic aneurysm, and aortic stenosis have no effective non-surgical medical therapies. Importantly, a growing body of human genetic data has identified that even beyond CAD, these additional CV diseases have significant genetic associations with genomic loci/genes/variants that are also associated with plasma lipid traits. This research program is focused on a systematic approach to fill some of the major gaps in knowledge that link these human genomic loci to new biology, disease pathogenesis and potential therapeutic targets. The goal is to provide a roadmap for how the hundreds of novel loci/genes/variants associated with CVD might ultimately be investigated in an efficient manner. The focus will be on genes associated with both plasma lipid traits and at least one major cardiovascular disease. Due to the liver’s primary role in lipid and lipoprotein metabolism, the investigators will target liver-expressed genes. Furthermore, they will leverage naturally- occurring protein-coding variation in genes that influence plasma lipids and CVD in order to gain greater insight into the structure-function relationships of these proteins and relationship to phenotypes. This is an ambitious program of research with two major Research Foci: Focus 1: Interrogation of novel putatively causal genes at loci associated with both lipid traits and CV disease. Through systematic data ingestion and analyses of large- scale GWAS and sequencing data, the study team will generate (and refine) a prioritized list of liver-expressed genes at loci significantly associated with plasma lipids and at least one CV disease. Cell-based and murine model systems will be used, accompanied by human studies, to validate causal genes and gain insight into the physiological and molecular mechanisms by which they exert their influence. Focus 2: Leveraging protein-coding variants to provide insight into structure-function properties of proteins influencing lipid traits and CV disease. Through systematic analyses of large-scale public and private genomic data linked to phenotypes, the investigators will develop a prioritized list of novel protein-coding variants associated with lipids and CVD and perform comparative functional studies in model systems and in human carriers. The outcome of these studies is expected to establish a firm biological basis for a substantial number of novel genes/proteins and protein- codin...