DNA Methylation Signatures of Cardiovascular Health Provide Insights Into Diseases

Madeleine Carbonneau^{1

2}, Yi Li³, Yishu Qu⁴, Yinan Zheng⁴, Alexis C Wood⁵, Mengyao Wang^{3

6}, Chunyu Liu³, Tianxiao Huan^{1

2}, Roby Joehanes^{1

2}, Xiuqing Guo⁷, Jie Yao⁷, Kent D Taylor⁷, Russell P Tracy⁸, Peter Durda⁸, Yongmei Liu⁹, W Craig Johnson¹⁰, Wendy S Post¹¹, Tom Blackwell¹², Jerome I Rotter⁷, Stephen S Rich¹³, Susan Redline^{14

15

16}, Myriam Fornage¹⁷, Jun Wang⁴, Hongyan Ning⁴, Lifang Hou⁴, Donald Lloyd-Jones⁴, Kendra Ferrier¹⁸, Yuan-I Min¹⁹, April P Carson¹⁹, Laura M Raffield²⁰, Alexander Teumer^{21

22}, Hans J Grabe^{21

23}, Henry Völzke^{24

22}, Matthias Nauck^{25

22}, Marcus Dörr^{26

22}, Arce Domingo-Relloso^{27

28

29}, Amanda Fretts³⁰, Maria Tellez-Plaza³¹, Shelley A Cole³², Ana Navas-Acien²⁸, Meng Wang^{3

6}, Joanne M Murabito^{2

33}, Nancy L Heard-Costa^{2

33}, Brenton Prescott³⁴, Vanessa Xanthakis^{2

3

34}, Dariush Mozaffarian⁶, Daniel Levy^#^{1

2}, Jiantao Ma^#⁶

Affiliations

¹ Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (M.C., T.H., R.J., D.L.).
² Framingham Heart Study, Framingham, MA (M.C., T.H., R.J., J.M.M., N.L.H.-C., V.X., D.L.).
³ Department of Biostatistics, Boston University School of Public Health, Boston, MA (Y. Li, M.W., C.L., V.X.).
⁴ Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (Y.Q., Y.Z., J.W., H.N., L.H., D.L.-J.).
⁵ United States Department of Agriculture/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX (A.C.W.).
⁶ Nutrition Epidemiology, and Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA (M.W., D.M., J.M.).
⁷ Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (X.G., J.Y., K.D.T., J.I.R.).
⁸ Department of Pathology and Laboratory Medicine, University of Vermont Larner College of Medicine, Colchester, VT (R.P.T., P.D.).
⁹ Duke Molecular Physiology Institute, Duke University, Durham, NC (Y. Liu).
¹⁰ Departments of Biostatistics (W.C.J.), University of Washington, Seattle, WA.
¹¹ Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (W.S.P.).
¹² Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI (T.B.).
¹³ Department of Genome Sciences, University of Virginia School of Medicine, Charlottesville, VA (S.S.R.).
¹⁴ Departments of Medicine and Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA (S.R.).
¹⁵ Department of Medicine, Brigham and Women's Hospital, Boston, MA (S.R.).
¹⁶ Department of Medicine, Harvard Medical School, Boston, MA (S.R.).
¹⁷ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX (M.F.).
¹⁸ Department of Bioinformatics and Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO (K.F.).
¹⁹ Department of Medicine, University of Mississippi Medical Center, Jackson, MS (Y.-I.M., A.P.C.).
²⁰ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC (L.M.R.).
²¹ Department of Psychiatry and Psychotherapy (A.T., H.J.G.), University Medicine Greifswald, Greifswald, Germany.
²² DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany (A.T., H.V., M.N., M.D.).
²³ German Center for Neurodegenerative Diseases (DZNE), Partner Site Rostock/Greifswald, Greifswald, Germany (H.J.G.).
²⁴ Department SHIP/Clinical-Epidemiological Research, Institute for Community Medicine (H.V.), University Medicine Greifswald, Greifswald, Germany.
²⁵ Institute of Clinical Chemistry and Laboratory Medicine (M.N.), University Medicine Greifswald, Greifswald, Germany.
²⁶ Department of Internal Medicine B (M.D.), University Medicine Greifswald, Greifswald, Germany.
²⁷ Departments of Biostatistics (A.D.-R.).
²⁸ Environmental Health Sciences (A.D.-R., A.N.-A.).
²⁹ Columbia University Mailman School of Public Health, New York, NY (A.D.-R.).
³⁰ Epidemiology, Cardiovascular Health Research Unit (A.F.), University of Washington, Seattle, WA.
³¹ Department of Chronic Disease Epidemiology, National Center for Epidemiology, Instituto de Salud Carlos III, Madrid, Spain (M.T.-P.).
³² Population Health Program, Texas Biomedical Research Institute, San Antonio, TX (S.A.C.).
³³ Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, (J.M.M., N.L.H.-C.).
³⁴ Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, MA (B.P., V.X.).

^# Contributed equally.

PMID: 40654086
PMCID: PMC12262172 (available on 2026-07-14)
DOI: 10.1161/CIRCULATIONAHA.124.073181

DNA Methylation Signatures of Cardiovascular Health Provide Insights Into Diseases

Madeleine Carbonneau et al. Circulation. 2025.

. 2025 Aug 19;152(7):436-449.

doi: 10.1161/CIRCULATIONAHA.124.073181. Epub 2025 Jul 14.

Authors

Affiliations

¹ Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (M.C., T.H., R.J., D.L.).
² Framingham Heart Study, Framingham, MA (M.C., T.H., R.J., J.M.M., N.L.H.-C., V.X., D.L.).
³ Department of Biostatistics, Boston University School of Public Health, Boston, MA (Y. Li, M.W., C.L., V.X.).
⁴ Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (Y.Q., Y.Z., J.W., H.N., L.H., D.L.-J.).
⁵ United States Department of Agriculture/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX (A.C.W.).
⁶ Nutrition Epidemiology, and Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA (M.W., D.M., J.M.).
⁷ Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA (X.G., J.Y., K.D.T., J.I.R.).
⁸ Department of Pathology and Laboratory Medicine, University of Vermont Larner College of Medicine, Colchester, VT (R.P.T., P.D.).
⁹ Duke Molecular Physiology Institute, Duke University, Durham, NC (Y. Liu).
¹⁰ Departments of Biostatistics (W.C.J.), University of Washington, Seattle, WA.
¹¹ Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (W.S.P.).
¹² Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI (T.B.).
¹³ Department of Genome Sciences, University of Virginia School of Medicine, Charlottesville, VA (S.S.R.).
¹⁴ Departments of Medicine and Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA (S.R.).
¹⁵ Department of Medicine, Brigham and Women's Hospital, Boston, MA (S.R.).
¹⁶ Department of Medicine, Harvard Medical School, Boston, MA (S.R.).
¹⁷ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX (M.F.).
¹⁸ Department of Bioinformatics and Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO (K.F.).
¹⁹ Department of Medicine, University of Mississippi Medical Center, Jackson, MS (Y.-I.M., A.P.C.).
²⁰ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC (L.M.R.).
²¹ Department of Psychiatry and Psychotherapy (A.T., H.J.G.), University Medicine Greifswald, Greifswald, Germany.
²² DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany (A.T., H.V., M.N., M.D.).
²³ German Center for Neurodegenerative Diseases (DZNE), Partner Site Rostock/Greifswald, Greifswald, Germany (H.J.G.).
²⁴ Department SHIP/Clinical-Epidemiological Research, Institute for Community Medicine (H.V.), University Medicine Greifswald, Greifswald, Germany.
²⁵ Institute of Clinical Chemistry and Laboratory Medicine (M.N.), University Medicine Greifswald, Greifswald, Germany.
²⁶ Department of Internal Medicine B (M.D.), University Medicine Greifswald, Greifswald, Germany.
²⁷ Departments of Biostatistics (A.D.-R.).
²⁸ Environmental Health Sciences (A.D.-R., A.N.-A.).
²⁹ Columbia University Mailman School of Public Health, New York, NY (A.D.-R.).
³⁰ Epidemiology, Cardiovascular Health Research Unit (A.F.), University of Washington, Seattle, WA.
³¹ Department of Chronic Disease Epidemiology, National Center for Epidemiology, Instituto de Salud Carlos III, Madrid, Spain (M.T.-P.).
³² Population Health Program, Texas Biomedical Research Institute, San Antonio, TX (S.A.C.).
³³ Department of Neurology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, (J.M.M., N.L.H.-C.).
³⁴ Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, MA (B.P., V.X.).

^# Contributed equally.

PMID: 40654086
PMCID: PMC12262172 (available on 2026-07-14)
DOI: 10.1161/CIRCULATIONAHA.124.073181

Abstract

Background: The association of overall cardiovascular health (CVH) with changes in DNA methylation (DNAm) has not been well characterized.

Methods: We calculated the American Heart Association's Life's Essential 8 score to reflect CVH in 5 cohorts with diverse backgrounds (mean age 54 years, 55% women, and enrollment year ranging from 1989 to 2012). Epigenome-wide association studies (EWAS) for Life's Essential 8 score were conducted, followed by bioinformatic analyses. DNAm loci significantly associated with Life's Essential 8 score were used to calculate a CVH DNAm score. We examined the association of the CVH DNAm score with incident cardiovascular disease (CVD), cardiovascular disease-specific mortality, and all-cause mortality.

Results: We identified 609 cytosine-phosphate-guanines (CpGs) associated with Life's Essential 8 score at false discovery rate<0.05 in the discovery analysis and at Bonferroni-corrected P<0.05 in the multicohort replication stage. Most had low to moderate heterogeneity (414 CpGs [68.0%] with heterogeneity <0.2) in replication analysis. Pathway enrichment analyses and a phenome-wide association study search associated these CpGs with inflammatory or autoimmune phenotypes. We observed enrichment for phenotypes in the Epigenome-Wide Association Study Catalog, with 29-fold enrichment for stroke (P=2.4e-15) and 21-fold for ischemic heart disease (P=7.4e-38). Two-sample Mendelian randomization (MR) analysis showed significant association between 141 CpGs and ten phenotypes (261 CpG-phenotype pairs) at false discovery rate<0.05. For example, hypomethylation at cg20544516 (MIR33B [microRNA 33b] and SREBF1 [sterol regulatory element-binding transcription factor 1]) is associated with a lower risk of stroke (P=8.1e-6). In multivariable prospective analyses, the CVH DNAm score was consistently associated with clinical outcomes across participating cohorts. Per SD increase in the CVH DNAm score, the decrease in risk of incident cardiovascular disease, cardiovascular disease mortality, and all-cause mortality ranged from 19% to 32%, 28% to 40%, and 27% to 45%, respectively.

Conclusions: We identified new DNAm signatures for CVH across diverse cohorts. Our analyses indicate that multiple biological pathways may be relevant to the observed association between CVH and clinical outcomes.

Keywords: DNA methylation; Life’s Essential 8; all-cause mortality; cardiovascular diseases; cardiovascular health; epigenome-wide association study.

PubMed Disclaimer

Conflict of interest statement

H.J.G. has received travel grants and speaker honoraria from Neuraxpharm, Servier, Indorsia, and Janssen Cilag.

Update of

DNA Methylation Signatures of Cardiovascular Health Provide Insights into Diseases.
Carbonneau M, Li Y, Qu Y, Zheng Y, Wood AC, Wang M, Liu C, Huan T, Joehanes R, Guo X, Yao J, Taylor KD, Tracy RP, Peter D, Liu Y, Johnson WC, Post WS, Blackwell T, Rotter JI, Rich SS, Redline S, Fornage M, Wang J, Ning H, Hou L, Lloyd-Jones D, Ferrier K, Min YI, Carson AP, Raffield LM, Teumer A, Grabe HJ, Völzke H, Nauck M, Dörr M, Domingo-Relloso A, Fretts A, Tellez-Plaza M, Cole S, Navas-Acien A, Wang M, Murabito JM, Heard-Costa NL, Prescott B, Xanthakis V, Mozaffarian D, Levy D, Ma J. Carbonneau M, et al. medRxiv [Preprint]. 2024 Nov 20:2024.11.19.24317587. doi: 10.1101/2024.11.19.24317587. medRxiv. 2024. Update in: Circulation. 2025 Aug 19;152(7):436-449. doi: 10.1161/CIRCULATIONAHA.124.073181. PMID: 39606375 Free PMC article. Updated. Preprint.

References

1. Lloyd-Jones DM, Allen NB, Anderson CAM, Black T, Brewer LC, Foraker RE, Grandner MA, Lavretsky H, Perak AM, Sharma G, Rosamond W, American Heart A. Life’s Essential 8: Updating and Enhancing the American Heart Association’s Construct of Cardiovascular Health: A Presidential Advisory From the American Heart Association. Circulation. 2022;146:e18–e43. - PMC - PubMed
1. Huang L, Wang A, Wu Z, Chen S, Zheng Y, Wu S, Gao X. Life’s essential 8 and risk of all-cause mortality in individuals with cardiovascular diseases: A prospective community-based study. Clin Cardiol. 2024;47:e24119–e24126. - PMC - PubMed
1. Song C, Cheng X, Bai Y. Association of change in cardiovascular health based on life’s essential 8 with incident cardiovascular disease. Am J Prev Cardiol. 2024;18:100668–100674. - PMC - PubMed
1. Lloyd-Jones DM, Ning H, Labarthe D, Brewer L, Sharma G, Rosamond W, Foraker RE, Black T, Grandner MA, Allen NB, Anderson C, Lavretsky H, Perak AM. Status of Cardiovascular Health in US Adults and Children Using the American Heart Association’s New “Life’s Essential 8” Metrics: Prevalence Estimates From the National Health and Nutrition Examination Survey (NHANES), 2013 Through 2018. Circulation. 2022;146:822–835. - PubMed
1. Ma J, Rebholz CM, Braun KVE, Reynolds LM, Aslibekyan S, Xia R, Biligowda NG, Huan T, Liu C, Mendelson MM, Joehanes R, Hu EA, Vitolins MZ, Wood AC, Lohman K, Ochoa-Rosales C, van Meurs J, Uitterlinden A, Liu Y, Elhadad MA, Heier M, Waldenberger M, Peters A, Colicino E, Whitsel EA, Baldassari A, Gharib SA, Sotoodehnia N, Brody JA, Sitlani CM, Tanaka T, Hill WD, Corley J, Deary IJ, Zhang Y, Schottker B, Brenner H, Walker ME, Ye S, Nguyen S, Pankow J, Demerath EW, Zheng Y, Hou L, Liang L, Lichtenstein AH, Hu FB, Fornage M, Voortman T, Levy D. Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality. Circ Genom Precis Med. 2020;13:e002766–e002783. - PMC - PubMed

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DNA Methylation Signatures of Cardiovascular Health Provide Insights Into Diseases

Affiliations

DNA Methylation Signatures of Cardiovascular Health Provide Insights Into Diseases

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical