Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease

Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease | 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 Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease Md Mesbah Uddin, Ngoc Quynh Nguyen, Bing Yu, Jennifer Brody, Akhil Pampana, and 27 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1463822/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Sep, 2022 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Age-related changes to the epigenome are well-documented, especially the pattern of genome-wide DNA methylation (DNAm) changes observed in blood. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study participants, with replication in 2655 Atherosclerosis Risk in Communities Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations for these two leading CHIP genes may promote the risk for CAD. Full Text Additional Declarations Yes there is potential Competing Interest. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. P.N. reports grant support from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, spousal employment and equity at Vertex, consulting income from Apple, AstraZeneca, Novartis, Genentech / Roche, Blackstone Life Sciences, Foresite Labs, and TenSixteen Bio, and is a scientific advisor board member and shareholder of TenSixteen Bio and geneXwell, all unrelated to this work. J.S.F. has consulted for Shionogi Inc. J.M. has guest-lectured at Merck, unrelated to this work. D.K. serves on a DSMB for Agnovos Healthcare, a scientific advisory board for Pfizer and Solarea Bio, and reports grant support from Amgen and Solarea Bio. B.L.E. has received research funding from Celgene, Deerfield, Novartis, and Calico and consulting fees from GRAIL, and is a member of the scientific advisory board and shareholder for Neomorph Therapeutics, TenSixteen Bio, Skyhawk Therapeutics, and Exo Therapeutics. S.J. and A.G.B. are co-founders and equity holders in TenSixteen Bio. The other authors declare no competing interests. Supplementary Files MS13907SupplementaryTable13711.xlsx Supplementary Tables 1-3 and 7-11 MS13907SupplementaryData.pdf Supplementary Data Cite Share Download PDF Status: Published Journal Publication published 12 Sep, 2022 Read the published version in Nature Communications → 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-1463822","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":94878055,"identity":"edb2075e-fc6c-4c56-927b-b7b910a9063c","order_by":0,"name":"Md Mesbah Uddin","email":"","orcid":"https://orcid.org/0000-0003-1846-0411","institution":"Broad Institute","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Md","middleName":"Mesbah","lastName":"Uddin","suffix":""},{"id":94878056,"identity":"5cac833a-b710-4877-9417-b9fe59361be9","order_by":1,"name":"Ngoc Quynh Nguyen","email":"","orcid":"","institution":"The University of 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P.N. reports grant support from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis, spousal employment and equity at Vertex, consulting income from Apple, AstraZeneca, Novartis, Genentech / Roche, Blackstone Life Sciences, Foresite Labs, and TenSixteen Bio, and is a scientific advisor board member and shareholder of TenSixteen Bio and geneXwell, all unrelated to this work. J.S.F. has consulted for Shionogi Inc. J.M. has guest-lectured at Merck, unrelated to this work. D.K. serves on a DSMB for Agnovos Healthcare, a scientific advisory board for Pfizer and Solarea Bio, and reports grant support from Amgen and Solarea Bio. B.L.E. has received research funding from Celgene, Deerfield, Novartis, and Calico and consulting fees from GRAIL, and is a member of the scientific advisory board and shareholder for Neomorph Therapeutics, TenSixteen Bio, Skyhawk Therapeutics, and Exo Therapeutics. S.J. and A.G.B. are co-founders and equity holders in TenSixteen Bio. The other authors declare no competing interests.","formattedTitle":"Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease","fulltext":[{"header":"Full Text","content":"This preprint is available for \u003ca href='/article/rs-1463822/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e."}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-1463822/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1463822/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Age-related changes to the epigenome are well-documented, especially the pattern of genome-wide DNA methylation (DNAm) changes observed in blood. 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