Comprehensive evaluation of smoking exposures and their interactions on DNA methylation

Thanh T Hoang; Yunsung Lee; Daniel L McCartney; Elin T G Kersten; Christian M Page; Paige M Hulls; Mikyeong Lee; Rosie M Walker; Charles E Breeze; Brian D Bennett; Adam B Burkholder; James Ward; Anne Lise Brantsæter; Ida H Caspersen; Alison A Motsinger-Reif; Marie Richards; Julie D White; Shanshan Zhao; Rebecca C Richmond; Maria C Magnus; BIOS Consortium; Gerard H Koppelman; Kathryn L Evans; Riccardo E Marioni; Siri E Håberg; Stephanie J London

doi:10.1016/j.ebiom.2023.104956

Comprehensive evaluation of smoking exposures and their interactions on DNA methylation

EBioMedicine. 2024 Feb:100:104956. doi: 10.1016/j.ebiom.2023.104956. Epub 2024 Jan 9.

Authors

Thanh T Hoang¹, Yunsung Lee², Daniel L McCartney³, Elin T G Kersten⁴, Christian M Page⁵, Paige M Hulls⁶, Mikyeong Lee⁷, Rosie M Walker⁸, Charles E Breeze⁹, Brian D Bennett¹⁰, Adam B Burkholder¹¹, James Ward¹⁰, Anne Lise Brantsæter¹², Ida H Caspersen², Alison A Motsinger-Reif¹³, Marie Richards¹⁴, Julie D White¹⁵, Shanshan Zhao¹³, Rebecca C Richmond⁶, Maria C Magnus²; BIOS Consortium; Gerard H Koppelman⁴, Kathryn L Evans³, Riccardo E Marioni³, Siri E Håberg², Stephanie J London¹⁶

Collaborators

BIOS Consortium:
Bastiaan Heijmans, Peter 't Hoen, Joyce van Meurs, Rick Jansen, Lude Franke, Dorret Boomsma, René Pool, Jenny van Dongen, Jouke Hottenga, Marleen van Greevenbroek, Coen Stehouwer, Carla van der Kallen, Casper Schalkwijk, Cisca Wijmenga, Sasha Zhernakova, Ettje Tigchelaar, P Eline Slagboom, Marian Beekman, Joris Deelen, Diana Van Heemst, Jan Veldink, Leonard van den Berg, Cornelia van Duijn, Bert Hofman, Aaron Isaacs, André Uitterlinden, P Mila Jhamai, Michael Verbiest, H Eka Suchiman, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij, Nico Lakenberg, Hailiang Mei, Maarten van Iterson, Michiel van Galen, Jan Bot, Dasha Zhernakova, Peter van 't Hof, Patrick Deelen, Irene Nooren, Matthijs Moed, Martijn Vermaat, René Luijk, Marc Bonder, Freerk van Dijk, Wibowo Arindrarto, Szymon Kielbasa, Morris Swertz, Erik van Zwet

Affiliations

¹ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA; Department of Pediatrics, Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA; Cancer and Hematology Center, Texas Children's Hospital, Houston, TX, USA.
² Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
³ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK.
⁴ University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Dept. of Pediatric Pulmonology and Pediatric Allergy, Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, GRIAC Research Institute, Groningen, the Netherlands.
⁵ Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway; Department of Physical Health and Ageing, Division for Physical and Mental Health, Norwegian Institute of Public Health, Oslo, Norway.
⁶ Population Health Sciences, Bristol Medical School, University of Bristol, BS8 2BN, UK; MRC Integrative Epidemiology Unit at University of Bristol, BS8 2BN, UK.
⁷ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
⁸ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XU, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK; School of Psychology, University of Exeter, Perry Road, Exeter, UK.
⁹ UCL Cancer Institute, University College London, Paul O'Gorman Building, London, UK; Altius Institute for Biomedical Sciences, Seattle, WA, USA.
¹⁰ Department of Health and Human Services, Integrative Bioinformatics Support Group, National Institutes of Health, Research Triangle Park, NC, USA.
¹¹ Department of Health and Human Services, Office of Environmental Science Cyberinfrastructure, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
¹² Department of Food Safety, Division of Climate and Environmental Health, Norwegian Institute of Public Health, Oslo, Norway.
¹³ Department of Health and Human Services, Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
¹⁴ Westat, Durham, NC, USA.
¹⁵ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA; GenOmics and Translational Research Center, Analytics Practice Area, RTI International, Research Triangle Park, NC, USA.
¹⁶ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA. Electronic address: london2@niehs.nih.gov.

Abstract

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.

Keywords: Dietary intake; Epigenomics; Illumina EPIC array; Secondhand smoke exposure; Sex difference; Smoking cessation.

MeSH terms

Adult
CpG Islands
DNA Methylation
Epigenesis, Genetic
Humans
Infant, Newborn
Smoking / adverse effects
Smoking / genetics
Smoking Cessation*
Tobacco Smoke Pollution*
Tobacco Smoking

Substances

Tobacco Smoke Pollution

Abstract

MeSH terms

Substances

Grants and funding