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

Background: Elevated 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. Methods: In 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. Results: CARDIA 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). Conclusions: To 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. ### Competing Interest Statement Dr. Goonewardena is supported by VA MERIT grant 1I01CX002560), Taubman Medical Research Institute (Wolfe Scholarship). Dr. Murthy owns stock or stock options in General Electric, Cardinal Health, Ionetix, Boston Scientific, Merck, Eli Lilly, Johnson and Johnson, and Pfizer. He has received research grants and consulting fees from Siemens Medical Imaging. He has served on medical advisory boards for Ionetix. Dr. Murthy and Dr. R. Shah are supported in part by grants from the National Institute of Diabetes, Digestive, and Kidney Diseases (U01DK123013-03); National Institute on Aging (R01 AG059729); National Heart, Lung and Blood Institute (R01 HL136685); and an American Heart Association Strategically Focused Research Network grant in Cardiometabolic Disease (funded proteomics in CARDIA). Dr. Shah has served for a consultant for Amgen and Cytokinetics. Dr. Shah is a co-inventor on a patent for ex-RNAs signatures of cardiac remodeling and a pending patent on proteomic signatures of fitness and lung and liver diseases. Dr. Brandt reports research funding from the National Institutes of Health (K23MD017253) and the Blue Cross Blue Shield of Michigan Foundation. He has received consulting fees from New Amsterdam Pharmaceuticals. Dr. Emmer was supported by the National Institutes of Health R01-HL167733 and the A. Alfred Taubman Medical Research Institute. Dr Do is supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) (R35-GM124836). Dr. Do reports being a scientific cofounder, consultant, and equity holder (pending) for Pensieve Health and a consultant for Variant Bio, all unrelated to this work. Dr. Bittner reports research funding to her institution from NHLBI through a sub-contract from Wake Forest University, Amgen, Dalcor, Esperion, Novartis, and Sanofi and Regeneron. She serves on DSMBs for NIH-NIA, Eli Lilly, and Verve Therapeutics and has received honoraria from the American College of Cardiology, American Heart Association, National Lipid Association and New Amsterdam Pharma. Dr. Rosenson reports research funding to his institution from Amgen, Arrowhead, Eli Lilly, Merck, NIH, Novartis, Novo Nordisk, Regeneron, and 89Bio, consulting fees from Amgen, Avilar, CRISPER Therapeutics, Eli Lilly, Lipigon, New Amsterdam, Novartis, Precision Biosciences, Regeneron, UltraGenyx, Verve Therapeutics, non-promotional honoraria from Meda Pharma, royalties from Wolters Kluwer (UpToDate), and stock holding in MediMergent, LLC. He reports patent applications on: Methods and systems for biocellular marker detection and diagnosis using a microfluidic profiling device. EFS ID: 32278349. Application No. (PCT/US2019/026364) (provisional); Compositions and methods relating to the identification and treatment of immunothrombotic conditions. New International Application No. (PCT/US2021/63104926); and quantification of Lp(a) vs. non-Lp(a) apoB concentration: development of a novel validated equation (PCT/US2021/63248837). The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (75N92023D00002 & 75N92023D00005), Northwestern University (75N92023D00004), University of Minnesota (75N92023D00006), and Kaiser Foundation Research Institute (75N92023D00003). This manuscript has been reviewed by CARDIA for scientific content. ### Funding Statement The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (75N92023D00002 & 75N92023D00005), Northwestern University (75N92023D00004), University of Minnesota (75N92023D00006), and Kaiser Foundation Research Institute (75N92023D00003). This manuscript has been reviewed by CARDIA for scientific content. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of University of Michigan gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.