Project Summary Cardiovascular disease remains the leading cause of death and disability globally. Despite lowering in mortality rates, residual risk of events caused by atherosclerosis are high. High Lipoprotein(a) [Lp(a)] Levels contribute to residual risk as they increase cardiovascular risk, despite optimal lipid lowering therapy. Lp(a) is an atherogenic, proinflammatory, and prothrombotic lipoprotein particle. There are ethnic differences that differentiate levels, with Blacks and Hispanics having higher Lp(a) levels when compared to Whites. These ethnic differences are supported by the fact that Lp(a) levels are mostly genetically regulated, with 90% of its variance controlled by the LPA gene. A comprehensive map of single-base polymorphisms (SNP) in the hypervariable LPA Kringle IV type 2 (KIV-2) copy number variation region was published in 2019. Some of these SNP are unique to specific ethnic populations and are linked to high and low Lp(a) levels. The latter provides a tool to interrogate the effect of SNP on Lp(a) particle levels, particle composition and function. The current proposal utilizes a multi- ethnic cohort at Columbia University Medical Center, where unique LPA KIV-2 variants are identified. Using advanced lipidomic, proteomic and fluxomic technologies, we will characterize the circulating Lp(a) particle of high frequency SNP expressed in Blacks which may be link to their higher levels of Lp(a) compared to Hispanics and Whites. Lp(a) levels have been difficult to alter, but newly approved and developing treatments targeting the apo(a) component of Lp(a) lower its plasma concentrations significantly. Therefore, additional knowledge of the disease causing “Lp(a)” particle is a need in the field as not everyone with high Lp(a) levels develops disease.