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Clin Epigenetics. 2018 Oct 20;10(1):126. doi: 10.1186/s13148-018-0558-0.

Smoking induces coordinated DNA methylation and gene expression changes in adipose tissue with consequences for metabolic health.

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Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK.
Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Linkou, Taiwan.
Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK.
Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, OX3 7LF, UK.
Department of Epidemiology, Brown University School of Public Health, Providence, RI, 02912, USA.
Institute for Molecular Medicine Finland (FIMM) and Department of Public Health, University of Helsinki, Helsinki, Finland.
Department of Bioinformatics, Institute of Health Sciences, Hacettepe University, 06100, Ankara, Turkey.
Pfizer - University of Granada - Andalusian Government Center for Genomics and Oncological Research (GENYO), Granada, Spain.
Division of Cancer Studies, King's College London, London, SE1 9RT, UK.
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY, 10029, USA.
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, 10029, USA.
Centre for Stem Cells and Regenerative Medicine, King's College London, Floor 28, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, SE1 9RT, UK.
Research Programs Unit, Diabetes and Obesity, Obesity Research Unit, University of Helsinki, Helsinki, Finland.
Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki, Finland.
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
Department of Genetic Medicine and Development, University of Geneva Medical School, 1211, Geneva, Switzerland.
Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211, Geneva, Switzerland.
Swiss Institute of Bioinformatics, 1211, Geneva, Switzerland.
Department of Laboratory Medicine & Pathology, Brown University, Providence, RI, 02912, USA.
Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK.



Tobacco smoking is a risk factor for multiple diseases, including cardiovascular disease and diabetes. Many smoking-associated signals have been detected in the blood methylome, but the extent to which these changes are widespread to metabolically relevant tissues, and impact gene expression or metabolic health, remains unclear.


We investigated smoking-associated DNA methylation and gene expression variation in adipose tissue biopsies from 542 healthy female twins. Replication, tissue specificity, and longitudinal stability of the smoking-associated effects were explored in additional adipose, blood, skin, and lung samples. We characterized the impact of adipose tissue smoking methylation and expression signals on metabolic disease risk phenotypes, including visceral fat.


We identified 42 smoking-methylation and 42 smoking-expression signals, where five genes (AHRR, CYP1A1, CYP1B1, CYTL1, F2RL3) were both hypo-methylated and upregulated in current smokers. CYP1A1 gene expression achieved 95% prediction performance of current smoking status. We validated and replicated a proportion of the signals in additional primary tissue samples, identifying tissue-shared effects. Smoking leaves systemic imprints on DNA methylation after smoking cessation, with stronger but shorter-lived effects on gene expression. Metabolic disease risk traits such as visceral fat and android-to-gynoid ratio showed association with methylation at smoking markers with functional impacts on expression, such as CYP1A1, and at tissue-shared smoking signals, such as NOTCH1. At smoking-signals, BHLHE40 and AHRR DNA methylation and gene expression levels in current smokers were predictive of future gain in visceral fat upon smoking cessation.


Our results provide the first comprehensive characterization of coordinated DNA methylation and gene expression markers of smoking in adipose tissue. The findings relate to human metabolic health and give insights into understanding the widespread health consequence of smoking outside of the lung.


Adipose tissue; DNA methylation; Gene expression; RNA-sequencing; Smoking

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