Identification of DNA methylation signatures of smoking in women and associations with cardiovascular disease mortality

Dennis Khodasevich; Aladdin H Shadyab; Adam X Maihofer; Caroline M Nievergelt; Robert Wallace; Lisa W Martin; Anne K Bozack; Rosemarie de la Rosa; Marcia L Stefanick; Nora Franceschini; Andres Cardenas

doi:10.1038/s42003-026-10454-y

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Identification of DNA methylation signatures of smoking in women and associations with cardiovascular disease mortality

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Identification of DNA methylation signatures of smoking in women and associations with cardiovascular disease mortality

Dennis Khodasevich, Aladdin H Shadyab, Adam X Maihofer, Caroline M Nievergelt, Robert Wallace, Lisa W Martin, Anne K Bozack, Rosemarie de la Rosa, Marcia L Stefanick, Nora Franceschini, …

Communications biology

06/09/2026

DOI: 10.1038/s42003-026-10454-y

PMID: 42265390

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Abstract

Tobacco smoking is critical risk factor for cardiovascular disease (CVD) and mortality, with epigenetics implicated as a key biological mechanism. Smoking disproportionately impacts CVD risk in women; however, limited research has examined smoking-associated DNA methylation (DNAm) changes in women. We measure whole blood DNAm (EPICv2) and self-reported smoking (three-category, pack-years, and years since cessation) via questionnaires in 6,005 Women's Health Initiative Memory Study participants. We perform epigenome-wide association studies and develop epigenetic predictors of each smoking phenotype, and compare DNAm and self-reported pack-years for CVD-related and all-cause mortality prediction. Here we find 20,388 FDR-significant sites related to current smoking, 2149 for former smoking, 14,709 for pack-years, and 753 for smoking cessation. The epigenetic predictors of smoking activity are highly correlated with their respective phenotypes and DNAm pack-years outperforms self-reported pack-years in mortality prediction. We report robust validation of previous findings, novel smoking associations in women, and introduce epigenetic predictors of smoking activity.

Details

Title: Subtitle: Identification of DNA methylation signatures of smoking in women and associations with cardiovascular disease mortality
Creators: Dennis Khodasevich - Stanford University
Aladdin H Shadyab - University of California San Diego
Adam X Maihofer - University of California San Diego
Caroline M Nievergelt - University of California San Diego
Robert Wallace - University of Iowa
Lisa W Martin - George Washington University
Anne K Bozack - New York University
Rosemarie de la Rosa - University of California, Berkeley
Marcia L Stefanick - Stanford University
Nora Franceschini - University of North Carolina at Chapel Hill
Andres Cardenas - Stanford University
Resource Type: Journal article
Publication Details: Communications biology
DOI: 10.1038/s42003-026-10454-y
PMID: 42265390
NLM abbreviation: Commun Biol
ISSN: 2399-3642
eISSN: 2399-3642
Publisher: Nature
Grant note: R01HL175681 / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01AG074345 / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R21ES035517 / U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)
Language: English
Electronic publication date: 06/09/2026
Academic Unit: Epidemiology; Injury Prevention Research Center
Record Identifier: 9985174492602771

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