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

BackgroundElevated lipoprotein (a) [Lp(a)] is associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD) events. Although Lp(a) is a genetically determined risk factor, the metabolomic and proteomic features that may mediate or be associated with this risk are unknown. MethodsIn young, healthy Coronary Artery Risk Development in Young Adults (CARDIA) participants, we defined the relationships between year 7 (Y7) 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. ResultsCARDIA participants had a mean age of 32 years at Y7 in this study and a median follow-up of 27.1 years. In the overall cohort (n=3920), Y7 Lp(a) levels were associated prospectively with ASCVD phenotypes at year 25 (Y25), including hs-CRP, coronary artery calcification (CAC), and incident CHD. 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. The Y7 Lp(a) transomic score was more strongly associated with Y25 incident CAC (standardized {beta} = 0.29, p=0.04), hs-CRP (standardized {beta} = 0.18, p =0.0008), and incident any CHD (standardized {beta} = 0.51, p = 0.05), than the Y7 Lp(a) concentration itself (no significant associations). ConclusionsTo our knowledge, this is the first study to identify relationships between Lp(a) and associated metabolomic/proteomic features in young, healthy adults and joint associations with ASCVD phenotypes. 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) concentrations alone.