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BACKGROUND: The pathways linking lipoprotein(a) (Lp[a]) to atherosclerotic cardiovascular disease (ASCVD) are unclear. This study aimed to discover Lp(a)-associated plasma proteins and estimate their associations with incident ASCVD.METHODS: We analyzed 48,859 UK Biobank participants with measured Lp(a) and proteomic profiles, with replication in 9,416 individuals in the Atherosclerosis Risk in Communities (ARIC) study cohort utilizing a separate proteomic platform. Linear models assessed associations between Lp(a) and protein concentrations adjusted for age, sex, cigarette smoking, diabetes diagnosis, body mass index, systolic blood pressure, hypertension, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglycerides, estimated glomerular filtration rate, statin prescription, and the first 10 components of genetic ancestry. Multiple testing correction was performed using the Benjamini-Hochberg FDR method (P < 0.05). We examined how the protein effect sizes from the primary analysis using the outcome of Lp(a) aligned with those for the outcomes of an LPA genetic risk score (GRS) and LDL-C. Cox proportional hazards models quantified hazard ratios (HRs) for protein associations with incident ASCVD.RESULTS: Participants were a mean age of 57 years (SD 8.22), 93.9% European, and 53.8% male, with median follow-up of 8.9 years (IQR 8.3-9.7). Of 1,459 circulating proteins, 164 were significantly associated with Lp(a) after FDR correction, with enrichment for lipid degradation, metabolism, and insulin secretion. In the ARIC study, 10 proteins were replicated with consistent effect estimates. Of these replicated proteins, there were no significant associations observed with an GRS. Only REG4 and VWC2 showed concordant associations with LDL-C (P < 0.001), consistent with their association with Lp(a). Five proteins exhibited concordant associations with Lp(a) and incident ASCVD (ITIH3, DLL1, REG4, VWC2, CBLN4). ITIH3 was positively associated with coronary artery disease (HR 1.13, 95% CI 1.04-1.23), peripheral artery disease (HR 1.42, 95% CI 1.19-1.69), major adverse limb events (HR 1.65, 95% CI 1.14-2.40), carotid stenosis (HR 1.45, 95% CI 1.13-1.85), and ischemic stroke (HR 1.33, 95% CI 1.13-1.55). CBLN4 uniquely showed inverse associations with Lp(a) and disease: higher levels were linked to lower risk of CAD (HR 0.88, 95% CI 0.80-0.96), PAD (HR 0.78, 95% CI 0.64-0.96), and ischemic stroke (HR 0.72, 95% CI 0.60-0.85).CONCLUSION: Using high-throughput proteomics, we discovered and replicated 10 proteins associated with circulating Lp(a), several of which were independent of genetically-predicted Lp(a). While Lp(a) is highly heritable, these atherogenic proteins represent a non-heritable Lp(a) axis.