Background

Smoking impacts DNA methylation, but data are lacking on smoking-related differential methylation by sex or dietary intake, recent smoking cessation (<1 year), persistence of differential methylation from in utero smoking exposure, and effects of environmental tobacco smoke (ETS).

Methods

We meta-analysed data from up to 15,014 adults across 5 cohorts with DNA methylation measured in blood using Illumina’s EPIC array for current smoking (2560 exposed), quit < 1 year (500 exposed), in utero (286 exposed), and ETS exposure (676 exposed). We also evaluated the interaction of current smoking with sex or diet (fibre, folate, and vitamin C).

Findings

Using false discovery rate (FDR < 0.05), 65,857 CpGs were differentially methylated in relation to current smoking, 4025 with recent quitting, 594 with in utero exposure, and 6 with ETS. Most current smoking CpGs attenuated within a year of quitting. CpGs related to in utero exposure in adults were enriched for those previously observed in newborns. Differential methylation by current smoking at 4-71 CpGs may be modified by sex or dietary intake. Nearly half (35-50%) of differentially methylated CpGs on the 450 K array were associated with blood gene expression. Current smoking and in utero smoking CpGs implicated 3049 and 1067 druggable targets, including chemotherapy drugs.

Interpretation

Many smoking-related methylation sites were identified with Illumina’s EPIC array. Most signals revert to levels observed in never smokers within a year of cessation. Many in utero smoking CpGs persist into adulthood. Smoking-related druggable targets may provide insights into cancer treatment response and shared mechanisms across smoking-related diseases.

Funding

Intramural Research Program of the National Institutes of Health, Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, Chief Scientist Office of the Scottish Government Health Directorates and the Scottish Funding Council, Medical Research Council UK and the Wellcome Trust.

Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.

Overview publication

TitleComprehensive evaluation of smoking exposures and their interactions on DNA methylation.
DateFebruary 1st, 2024
Issue nameEBioMedicine
Issue numberv100:104956
DOI10.1016/j.ebiom.2023.104956
PubMed38199042
AuthorsHoang TT, Lee Y, McCartney DL, Kersten ETG, Page CM, Hulls PM, Lee M, Walker RM, Breeze CE, Bennett BD, Burkholder AB, Ward J, Brantsæter AL, Caspersen IH, Motsinger-Reif AA, Richards M, White JD, Zhao S, Richmond RC, Magnus MC, Koppelman GH, Evans KL, Marioni RE, Håberg SE & London SJ
InfoBIOS Consortium, Heijmans B, 't Hoen P, van Meurs J, Jansen R, Franke L, Boomsma D, Pool R, van Dongen J, Hottenga J, van Greevenbroek M, Stehouwer C, van der Kallen C, Schalkwijk C, Wijmenga C, Zhernakova S, Tigchelaar E, Slagboom PE, Beekman M, Deelen J, Van Heemst D, Veldink J, van den Berg L, van Duijn C, Hofman B, Isaacs A, Uitterlinden A, Jhamai PM, Verbiest M, Suchiman HE, Verkerk M, van der Breggen R, van Rooij J, Lakenberg N, Mei H, van Iterson M, van Galen M, Bot J, Zhernakova D, van 't Hof P, Deelen P, Nooren I, Moed M, Vermaat M, Luijk R, Bonder M, van Dijk F, Arindrarto W, Kielbasa S, Swertz M, van Zwet E
KeywordsDietary intake, Epigenomics, Illumina EPIC array, Secondhand smoke exposure, Sex difference, Smoking cessation
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