Lipoprotein(a) metabolomic and proteomic features and atherosclerotic cardiovascular disease in young, asymptomatic adults

Abstract Background Lipoprotein (a) [Lp(a)] is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) events. Although Lp(a) is a powerful genetic risk factor for ASCVD, the pathways that mediate this risk and the associated metabolomic and proteomic features that capture this risk are unknown. Methods In young, asymptomatic Coronary Artery Risk Development in Young Adults (CARDIA) participants, we defined the relationships between Lp(a) and metabolomic (n=563)/proteomic (n=184) features, derived quantitative Lp(a)-omic scores from these features, and related these quantitative scores to ASCVD phenotypes. Results CARDIA subjects had a mean age of 32 years and a median follow-up of 27 years. In the overall cohort (n=3920), Lp(a) levels at year 7 (Y7) were significantly associated with ASCVD endpoints, including hs-CRP, coronary artery calcification (CAC), death, and incident CHD (Figure 1A). In the subcohort (n=2290) that had measurements of Lp(a), proteomics, and metabolomics, Y7 Lp(a) levels were associated with distinct proteomic and metabolomic features indicative of immune responses, lipoprotein metabolism, atherogenesis, and arginine/steroid biosynthesis. Using machine learning approaches, Lp(a) metabolomic, proteomic, and transomic quantitative scores were derived. After adjustment, the Lp(a) transomic score was more strongly related to incident CAC, degree of CAC, CRP, and incident CHD than Lp(a) itself (Figure 1B). Conclusions To our knowledge, this is the first study to examine the relationship between Lp(a), metabolomic/proteomic features, and ASCVD phenotypes in young, asymptomatic adults. The multi-omics approaches employed here provide insight into the pathobiology of Lp(a)-driven ASCVD and enable more nuanced mechanistic risk assessment compared with Lp(a) alone.