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.
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.
| Original language | English |
|---|---|
| Article number | 104956 |
| Journal | EBioMedicine |
| Volume | 100 |
| DOIs | |
| Publication status | Published - 9 Jan 2024 |
Bibliographical note
Funding Information:Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates ( CZD/16/6 ) and the Scottish Funding Council ( HR03006 ). DNA methylation profiling of the GS samples was carried out by the Genetics Core Laboratory at the Clinical Research Facility, University of Edinburgh, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” ([STRADL; Reference 104036/Z/14/Z ]).
Funding Information:
This study makes use of data generated by the Biobank-based Integrative Omics Study (BIOS) consortium. A full list of the investigators is available from http://www.bbmri.nl/en-gb/activities/rainbow-projects/bios . Funding for the project was provided by the Netherlands Organisation for Scientific Research ( NWO 184.021.007 , dated July 9, 2009) and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). ETGK received a grant from the Netherlands Lung Foundation . GHK received grants or contracts from ZonMw , Vertex , Netherlands Lung Foundation , GSK , Teva the Netherlands, and European Union .
Funding Information:
This work was supported in part by the Intramural Research Program of the National Institutes of Health , National Institute of Environmental Health Sciences (NIEHS; Z01-ES102385 , Z01-ES049030 , Z01-ES043012 ) and the National Cancer Institute ( Z01-CP010119 ). This work was also supported in part by American Recovery and Reinvestment Act (ARRA) funds through NIEHS contract number N01-ES-55546 .
Funding Information:
The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research . The work was partly funded by the Research Council of Norway through its Centre's of Excellence funding scheme (project No 262700 ). MCM received grants from the Research Council of Norway and European Research Council .
Funding Information:
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.The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The work was partly funded by the Research Council of Norway through its Centre's of Excellence funding scheme (project No 262700). MCM received grants from the Research Council of Norway and European Research Council. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (NIEHS; Z01-ES102385, Z01-ES049030, Z01-ES043012) and the National Cancer Institute (Z01-CP010119). This work was also supported in part by American Recovery and Reinvestment Act (ARRA) funds through NIEHS contract number N01-ES-55546. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). DNA methylation profiling of the GS samples was carried out by the Genetics Core Laboratory at the Clinical Research Facility, University of Edinburgh, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” ([STRADL; Reference 104036/Z/14/Z]). For UKHLS, the epigenetics methylation data were analysed by the University of Exeter Medical School (MRC grant K013807) and further facilitated by the University of Essex School of Biological Sciences. Understanding Society is an initiative funded by the Economic and Social Research Council (ES/N00812X/1) and various Government Departments, with scientific leadership by the Institute for Social and Economic Research, University of Essex, and survey delivery by NatCen Social Research and Kantar Public. RCR is supported by a de Pass Vice Chancellor's Fellowship at the University of Bristol. This study makes use of data generated by the Biobank-based Integrative Omics Study (BIOS) consortium. A full list of the investigators is available from http://www.bbmri.nl/en-gb/activities/rainbow-projects/bios. Funding for the project was provided by the Netherlands Organisation for Scientific Research (NWO 184.021.007, dated July 9, 2009) and made available as a Rainbow Project of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL). ETGK received a grant from the Netherlands Lung Foundation. GHK received grants or contracts from ZonMw, Vertex, Netherlands Lung Foundation, GSK, Teva the Netherlands, and European Union. We are grateful to Stacey Mantooth and the NIEHS library for their assistance with the literature search. We appreciate all the study participants for their contribution to this research.
Funding Information:
For UKHLS, the epigenetics methylation data were analysed by the University of Exeter Medical School (MRC grant K013807 ) and further facilitated by the University of Essex School of Biological Sciences. Understanding Society is an initiative funded by the Economic and Social Research Council ( ES/N00812X/1 ) and various Government Departments, with scientific leadership by the Institute for Social and Economic Research, University of Essex , and survey delivery by NatCen Social Research and Kantar Public . RCR is supported by a de Pass Vice Chancellor's Fellowship at the University of Bristol .
Publisher Copyright:
© 2024 The Authors