Plasma Proteomic Profiling Reveals Distinct Roles of Apolipoprotein B-containing Lipoproteins in Atherosclerosis

Plasma Proteomic Profiling Reveals Distinct Roles of Apolipoprotein B-containing Lipoproteins in Atherosclerosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Plasma Proteomic Profiling Reveals Distinct Roles of Apolipoprotein B-containing Lipoproteins in Atherosclerosis Jakub Morze, Elias Björnson, Michael Mi, Martin Adiels, Giorgio Melloni, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8307321/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract All apolipoprotein B-containing lipoproteins are established causal factors for coronary artery disease (CAD). However, triglyceride-rich lipoproteins (TRL) and lipoprotein(a) [Lp(a)] exhibit greater per-particle atherogenicity than low-density lipoprotein (LDL) through mechanisms that remain unclear. To elucidate these mechanisms, we combined observational and Mendelian randomization analyses in UK Biobank to identify plasma proteomic signatures of LDL, TRL, and Lp(a). We identified 30, 471, and 53 proteins robustly associated with LDL, TRL, and Lp(a) concentrations, respectively. TRL and Lp(a) signatures were distinct from the LDL signature and substantially overlapped with each other (36 proteins), with shared enrichment in inflammatory pathways. Multi-protein scores summarizing each signature showed that TRL (HR 1.16, 95%CI 1.08-1.24) and Lp(a) (HR 1.09, 95%CI 1.03-1.15), but not LDL (HR 0.95, 95%CI 0.89-1.02), were associated with CAD risk after adjustment for measured lipoprotein concentrations. Mediation analysis implicated inflammation as a major mediator (proportion mediated: 62%) of the excess TRL-associated CAD risk. Main analyses were replicated in the Multi-Ethnic Study of Atherosclerosis. Our findings provide deeper insight into the biological processes triggered by atherogenic lipoproteins that extend beyond lipid deposition in the arterial wall. Health sciences/Diseases/Cardiovascular diseases/Dyslipidaemias Biological sciences/Systems biology Health sciences/Medical research/Epidemiology Health sciences/Biomarkers Full Text Additional Declarations Yes there is potential Competing Interest. J.M. received fees from Alab Laboratoria outside the submitted work. E.B. received consulting fees from Arrowhead Pharmaceuticals and Novartis. N.A.M. reported grants from Ionis, Amgen, and Pfizer and personal fees from Amgen, Beckman Coulter, and Viz.ai outside the submitted work. C.J.P. received honoraria and consulting fees from Amgen, Amarin, Arrowhead, Dalcor, Novartis, and Response Therapeutics outside the submitted work. J.B. received honoraria and consulting fees from Novartis, Novo Nordisk, Akcea, Amgen, Ribocure, and Pfizer outside the submitted work. The other authors declare no conflicts of interest. Supplementary Files supplementarytables120725final.xlsx Supplementary Tables Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8307321","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":560800980,"identity":"ad2bd309-c137-4cd6-b947-406f527348db","order_by":0,"name":"Jakub Morze","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYBAC9gY2BmYom/EBYwODDEEtjEhamA2AWnhI0sImQZyW9mNp0gUM2+TM+w8fq/i5w45Ht7338QeGPza4tfSkHZOewXDbWObAsbSbvWeSeczOHDeTYGxLw+Ow9DZpHobbiTMYe8xuM7Yx85jdSGMDCh/GraX/OVQLM/+3Ysa2eh6z+8+YgQ77j1OL4Aygw8Ba2HjYmBnbDgNtYWOQYGA7gFOLtMSzZOsZBreNJXjYjCV7244D/ZLGJpHYloxTCx9/muHtgorbchL8hx9++NlWLWd2/Bjzhw9/7HBqgQADdIEEAhpGwSgYBaNgFOAHAHxGTT6smGnpAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-7119-0273","institution":"Chalmers University of Technology","correspondingAuthor":true,"prefix":"","firstName":"Jakub","middleName":"","lastName":"Morze","suffix":""},{"id":560800981,"identity":"f76fcfb9-f7fc-4ca9-af9c-ee0321ffbf6e","order_by":1,"name":"Elias Björnson","email":"","orcid":"","institution":"University of Gothenburg","correspondingAuthor":false,"prefix":"","firstName":"Elias","middleName":"","lastName":"Björnson","suffix":""},{"id":560800982,"identity":"df26c698-a69e-46dc-9676-1d37d6c0fa5a","order_by":2,"name":"Michael Mi","email":"","orcid":"","institution":"Beth Israel Deaconess Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Mi","suffix":""},{"id":560800983,"identity":"dfc6adad-7011-4155-ada3-6fd18afcfe2e","order_by":3,"name":"Martin Adiels","email":"","orcid":"","institution":"University of Gothenburg","correspondingAuthor":false,"prefix":"","firstName":"Martin","middleName":"","lastName":"Adiels","suffix":""},{"id":560800984,"identity":"0a8b6b4b-284c-447d-8760-470ed7a15d61","order_by":4,"name":"Giorgio Melloni","email":"","orcid":"https://orcid.org/0000-0001-6371-1334","institution":"TIMI Study Group, Brigham and Women's Hospital, Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Giorgio","middleName":"","lastName":"Melloni","suffix":""},{"id":560800985,"identity":"1271de55-fcd0-484c-b7c4-9a5410d54568","order_by":5,"name":"Gonçalo Rosas da Silva","email":"","orcid":"","institution":"AstraZeneca BioPharmaceuticals R\u0026D","correspondingAuthor":false,"prefix":"","firstName":"Gonçalo","middleName":"Rosas da","lastName":"Silva","suffix":""},{"id":560800986,"identity":"157a6a52-ebeb-46c3-8d48-2ee6e12e0b47","order_by":6,"name":"Andrzej Rynkiewicz","email":"","orcid":"","institution":"Municipal Hospital","correspondingAuthor":false,"prefix":"","firstName":"Andrzej","middleName":"","lastName":"Rynkiewicz","suffix":""},{"id":560800987,"identity":"a8ee5e97-c81c-4112-ae2a-8a1dd5c3f52f","order_by":7,"name":"Nicholas Marston","email":"","orcid":"https://orcid.org/0000-0001-6164-4617","institution":"TIMI Study Group, Brigham and Women's Hospital, Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Nicholas","middleName":"","lastName":"Marston","suffix":""},{"id":560800988,"identity":"f7c65afa-c288-4fb0-8dc0-75e1431ee799","order_by":8,"name":"Marta Guasch-Ferré","email":"","orcid":"https://orcid.org/0000-0001-8525-1404","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Marta","middleName":"","lastName":"Guasch-Ferré","suffix":""},{"id":560800989,"identity":"9473dd71-11a4-4193-b985-eb77bf017aa5","order_by":9,"name":"Michael Tsai","email":"","orcid":"","institution":"University of Minneosta","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Tsai","suffix":""},{"id":560800990,"identity":"06beacc5-42ef-448d-afc4-3726fa0cfde2","order_by":10,"name":"Jerome Rotter","email":"","orcid":"https://orcid.org/0000-0001-7191-1723","institution":"The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Jerome","middleName":"","lastName":"Rotter","suffix":""},{"id":560800991,"identity":"94d1bab9-3671-42db-b515-ccdca48cb3d3","order_by":11,"name":"Robert Gerszten","email":"","orcid":"https://orcid.org/0000-0002-6767-7687","institution":"Massachusetts General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Gerszten","suffix":""},{"id":560800992,"identity":"10fe1461-126b-41d4-b2a0-9cfb0235fb29","order_by":12,"name":"Qi Sun","email":"","orcid":"https://orcid.org/0000-0002-8480-1563","institution":"Harvard T. H. Chan School of Public Health","correspondingAuthor":false,"prefix":"","firstName":"Qi","middleName":"","lastName":"Sun","suffix":""},{"id":560800993,"identity":"a4c1642d-4c3c-4dae-bde4-a33f13fc0525","order_by":13,"name":"Frank Hu","email":"","orcid":"https://orcid.org/0000-0002-8233-6274","institution":"Harvard T. H. Chan School of Public Health","correspondingAuthor":false,"prefix":"","firstName":"Frank","middleName":"","lastName":"Hu","suffix":""},{"id":560800994,"identity":"618a61f4-4ce3-4223-a1b9-ae34a29ed50a","order_by":14,"name":"Rikard Landberg","email":"","orcid":"https://orcid.org/0000-0002-6399-7608","institution":"Chalmers University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Rikard","middleName":"","lastName":"Landberg","suffix":""},{"id":560800995,"identity":"03f0cdd1-a462-4e11-a219-80c07c725261","order_by":15,"name":"Göran Bergström","email":"","orcid":"https://orcid.org/0000-0003-4289-5722","institution":"University of Gothenburg","correspondingAuthor":false,"prefix":"","firstName":"Göran","middleName":"","lastName":"Bergström","suffix":""},{"id":560800996,"identity":"e006f44f-7fc6-44df-adbe-be2d3e23c7f3","order_by":16,"name":"Chris Packard","email":"","orcid":"","institution":"University of Glasgow","correspondingAuthor":false,"prefix":"","firstName":"Chris","middleName":"","lastName":"Packard","suffix":""},{"id":560800997,"identity":"df161f37-b5ef-4812-a1ba-b8900ae4c9c7","order_by":17,"name":"Jan Borén","email":"","orcid":"https://orcid.org/0000-0003-0786-8091","institution":"Gothenburg University","correspondingAuthor":false,"prefix":"","firstName":"Jan","middleName":"","lastName":"Borén","suffix":""},{"id":560800998,"identity":"24bd7ef7-1114-42c2-a21e-e7dd52673396","order_by":18,"name":"Clemens Wittenbecher","email":"","orcid":"https://orcid.org/0000-0001-7792-877X","institution":"Chalmers University of Technology","correspondingAuthor":false,"prefix":"","firstName":"Clemens","middleName":"","lastName":"Wittenbecher","suffix":""}],"badges":[],"createdAt":"2025-12-08 11:41:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8307321/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8307321/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":98627176,"identity":"9272f4a6-96c6-40bd-87c9-3dd4e07c6ba0","added_by":"auto","created_at":"2025-12-19 17:10:11","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1508134,"visible":true,"origin":"","legend":"Article File","description":"","filename":"manuscript120725final.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8307321/v1_covered_ad492f30-9cec-40f3-b471-360afc98680a.pdf"},{"id":98563167,"identity":"cedd6dbb-753d-452a-833c-186e6d3f0c93","added_by":"auto","created_at":"2025-12-19 03:33:02","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2410821,"visible":true,"origin":"","legend":"Supplementary Tables","description":"","filename":"supplementarytables120725final.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8307321/v1/9e1a892c59bd291c7c1d05c3.xlsx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nJ.M. received fees from Alab Laboratoria outside the submitted work. E.B. received consulting fees from Arrowhead Pharmaceuticals and Novartis. N.A.M. reported grants from Ionis, Amgen, and Pfizer and personal fees from Amgen, Beckman Coulter, and Viz.ai outside the submitted work. C.J.P. received honoraria and consulting fees from Amgen, Amarin, Arrowhead, Dalcor, Novartis, and Response Therapeutics outside the submitted work. J.B. received honoraria and consulting fees from Novartis, Novo Nordisk, Akcea, Amgen, Ribocure, and Pfizer outside the submitted work. The other authors declare no conflicts of interest.","formattedTitle":"Plasma Proteomic Profiling Reveals Distinct Roles of Apolipoprotein B-containing Lipoproteins in Atherosclerosis","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8307321/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8307321/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"All apolipoprotein B-containing lipoproteins are established causal factors for coronary artery disease (CAD). However, triglyceride-rich lipoproteins (TRL) and lipoprotein(a) [Lp(a)] exhibit greater per-particle atherogenicity than low-density lipoprotein (LDL) through mechanisms that remain unclear. To elucidate these mechanisms, we combined observational and Mendelian randomization analyses in UK Biobank to identify plasma proteomic signatures of LDL, TRL, and Lp(a). We identified 30, 471, and 53 proteins robustly associated with LDL, TRL, and Lp(a) concentrations, respectively. TRL and Lp(a) signatures were distinct from the LDL signature and substantially overlapped with each other (36 proteins), with shared enrichment in inflammatory pathways. Multi-protein scores summarizing each signature showed that TRL (HR 1.16, 95%CI 1.08-1.24) and Lp(a) (HR 1.09, 95%CI 1.03-1.15), but not LDL (HR 0.95, 95%CI 0.89-1.02), were associated with CAD risk after adjustment for measured lipoprotein concentrations. Mediation analysis implicated inflammation as a major mediator (proportion mediated: 62%) of the excess TRL-associated CAD risk. Main analyses were replicated in the Multi-Ethnic Study of Atherosclerosis. Our findings provide deeper insight into the biological processes triggered by atherogenic lipoproteins that extend beyond lipid deposition in the arterial wall.","manuscriptTitle":"Plasma Proteomic Profiling Reveals Distinct Roles of Apolipoprotein B-containing Lipoproteins in Atherosclerosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-19 03:32:57","doi":"10.21203/rs.3.rs-8307321/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e1921118-ca1b-4cd4-a7eb-33a5838c7bd5","owner":[],"postedDate":"December 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":59706492,"name":"Health sciences/Diseases/Cardiovascular diseases/Dyslipidaemias"},{"id":59706493,"name":"Biological sciences/Systems biology"},{"id":59706494,"name":"Health sciences/Medical research/Epidemiology"},{"id":59706495,"name":"Health sciences/Biomarkers"}],"tags":[],"updatedAt":"2025-12-19T03:32:57+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-19 03:32:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8307321","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8307321","identity":"rs-8307321","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}