Abstract 4366225: Proteomic Signatures of Lipoprotein (a) Particles Reveal Novel Associations with Plasma Levels and KIV-2 Copy Number in an Elderly Multiethnic Cohort

Background: High lipoprotein(a) [Lp(a)] is a causal risk factor for Atherosclerotic Cardiovascular Disease, yet the mechanisms driving this risk remain unclear. Lp(a) levels are largely determined by variation in the LPA gene, but less is known about additional protein components and their relationship to genetic markers such as the kringle IV type 2 copy number (KIV-2 CN). Hypothesis: We hypothesized that the proteomic profile of Lp(a) particles would reveal novel proteins and pathways associated with Lp(a) levels providing mechanistic insight into Lp(a)-mediated risk. Methods: We conducted proteomic profiling of Lp(a) particles in 35 elderly participants (mean age 81 years; 71% female; 63% African American, 37% Caucasian) from the Washington Heights-Inwood Community Aging Project. Plasma Lp(a) was quantified using an isoform-independent ELISA, and KIV-2 CN was estimated using a published calling platform. Lp(a) particles were isolated by immunoprecipitation, and proteomic analysis was performed using liquid chromatography-tandem mass spectrometry. Protein associations with Lp(a) levels and KIV-2 CN were assessed using linear regression, adjusting for multiple testing with the Benjamini–Hochberg false discovery rate (FDR) method. Protein interaction networks were analyzed using the STRING database. Results: The median Lp(a) level was 37.1 nmol/L (interquartile range 13.1–86.2), and the mean KIV-2 CN was 20. In addition to 35 previously reported proteins, we identified two novel proteins: complement C1s (FDR-adjusted p= 2e-6) and apolipoprotein D (FDR-adjusted p=0.0148). Furthermore, several proteins, showed significant associations with KIV-2 CN, highlighting potential genotype-related effects, Table 1. STRING analysis revealed enrichment of immune and lipid metabolism pathways, including complement activation and apolipoprotein binding, Figure 1. Conclusion: The proteome of isolated Lp(a) particles reveals insights into pathways that link Lp(a) to cardiovascular and other disease processes.