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DNA methylation (DNAm) \u2013 a critical epigenetic modification bridging environment and health \u2013 remains understudied as a contributor to stress- related CHD.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted an epigenome-wide association study (EWAS) of stress in the Women\u2019s Health Initiative (WHI), an ancestrally diverse cohort of postmenopausal women (n=3,857). At screening visit, participants completed a questionnaire assessing stressful life events and provided whole blood for DNAm. Incident CHD was then longitudinally ascertained (follow-up mean\/SD: 16.7\/8.4 years), and DNAm signatures were evaluated as CHD predictors using Cox regression. Predictive models were independently validated in the Jackson Heart Study (JHS; n=3,053) and Multi-Ethnic Study of Atherosclerosis (MESA; n=870). The bulk-level DNAm associations were computationally deconvolved at the cell-type-specific level using tensor composition analysis (TCA).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    The EWAS in WHI identified 841 stress-related DNAm sites (99 hypermethylated, 742 hypomethylated with stress) after FDR correction, with 13 significant after Bonferroni correction, including sites located on immune and CHD- related genes (e.g.,\n                    <jats:italic>TNF<\/jats:italic>\n                    ,\n                    <jats:italic>ALDH2<\/jats:italic>\n                    ). Methylation risk scores (MRSs) integrating the 841 FDR-significant sites (MRS\n                    <jats:sub>841<\/jats:sub>\n                    ) and 13 Bonferroni-significant sites (MRS\n                    <jats:sub>13<\/jats:sub>\n                    ) predicted incident CHD (HR=1.33-1.37; p\u22640.0008) and mediated 16.5-17.7% of the association between stress and CHD. In JHS and MESA, MRS\n                    <jats:sub>13<\/jats:sub>\n                    independently predicted CHD (HR=1.34; p=0.036), whereas MRS\n                    <jats:sub>841<\/jats:sub>\n                    was suggestively associated with CHD (HR=1.27; p=0.087). TCA indicated that the greatest number of stress-related sites predictive of CHD was specifically in monocytes (133 total), with directions consistent with bulk-level associations (9 hypermethylated, 124 hypomethylated with stress).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our study supports methylation risk scores as novel biomarkers of stress- related CHD and uncovers epigenetic regulation in monocytes as a potential underlying mechanism. These findings highlight biological pathways linking stress and disease and may promote personalized interventions in high-risk populations.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.31.26359423","type":"posted-content","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T16:50:23Z","timestamp":1785775823000},"source":"Crossref","is-referenced-by-count":0,"title":["Stress-Related Methylation Risk Scores Predict Coronary Heart Disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4689-1112","authenticated-orcid":false,"given":"Sofia","family":"Benavides","sequence":"first","affiliation":[{"name":"Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA"},{"name":"UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8830-6869","authenticated-orcid":false,"given":"Hazel","family":"Milla","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA"},{"name":"Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4961-8077","authenticated-orcid":false,"given":"Helena","family":"Palma-Gudiel","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7005-2565","authenticated-orcid":false,"given":"David","family":"Checknita","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA"},{"name":"AbbVie Corporation, Saint-Laurent, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6486-3708","authenticated-orcid":false,"given":"Bjoernar","family":"Tuftin","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1326-0891","authenticated-orcid":false,"given":"Kai","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7986-8560","authenticated-orcid":false,"given":"Charles","family":"Kooperberg","sequence":"additional","affiliation":[{"name":"Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0607-6714","authenticated-orcid":false,"given":"Alexander P.","family":"Reiner","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, University of Washington & Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9426-7595","authenticated-orcid":false,"given":"JoAnn E.","family":"Manson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2349-0009","authenticated-orcid":false,"given":"Themistocles L.","family":"Assimes","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA"},{"name":"VA Palo Alto Healthcare System, Palo Alto, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1709-1781","authenticated-orcid":false,"given":"Parveen","family":"Bhatti","sequence":"additional","affiliation":[{"name":"Population Health Sciences, BC Cancer Research Institute, Vancouver, British Columbia, Canada"},{"name":"School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2756-4370","authenticated-orcid":false,"given":"Kent D.","family":"Taylor","sequence":"additional","affiliation":[{"name":"The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3161-3753","authenticated-orcid":false,"given":"W. 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