Epigenetic Signatures of Cigarette Smoking.
Joehanes, Roby PhD; Just, Allan C. PhD; Marioni, Riccardo E. PhD; Pilling, Luke C. PhD; Reynolds, Lindsay M. PhD; Mandaviya, Pooja R. MSc; Guan, Weihua PhD; Xu, Tao PhD; Elks, Cathy E. PhD; Aslibekyan, Stella PhD; Moreno-Macias, Hortensia ScD; Smith, Jennifer A. PhD, MPH; Brody, Jennifer A. BA; Dhingra, Radhika PhD; Yousefi, Paul MPH; Pankow, James S. PhD; Kunze, Sonja PhD; Shah, Sonia H. PhD; McRae, Allan F. PhD; Lohman, Kurt MStat; Sha, Jin MS; Absher, Devin M. PhD; Ferrucci, Luigi MD, PhD; Zhao, Wei PhD; Demerath, Ellen W. PhD; Bressler, Jan PhD; Grove, Megan L. MS; Huan, Tianxiao PhD; Liu, Chunyu PhD; Mendelson, Michael M. MD; Yao, Chen PhD; Kiel, Douglas P. MD, MPH; Peters, Annette PhD; Wang-Sattler, Rui PhD; Visscher, Peter M. PhD; Wray, Naomi R. PhD; Starr, John M. PhD; Ding, Jingzhong PhD; Rodriguez, Carlos J. MD, MPH; Wareham, Nicholas J. PhD; Irvin, Marguerite R. PhD; Zhi, Degui PhD; Barrdahl, Myrto PhD; Vineis, Paolo MD; Ambatipudi, Srikant PhD; Uitterlinden, Andre G. PhD; Hofman, Albert MD, PhD; Schwartz, Joel PhD; Colicino, Elena PhD; Hou, Lifang MD, PhD; Vokonas, Pantel S. MD; Hernandez, Dena G. PhD; Singleton, Andrew B. PhD; Bandinelli, Stefania MD; Turner, Stephen T. MD; Ware, Erin B. PhD, MPH; Smith, Alicia K. PhD; Klengel, Torsten MD; Binder, Elisabeth B. MD, PhD; Psaty, Bruce M. MD, PhD; Taylor, Kent D. PhD; Gharib, Sina A. MD; Swenson, Brenton R. MPP; Liang, Liming PhD; DeMeo, Dawn L. MD, MPH; O'Connor, George T. MD, MS; Herceg, Zdenko DVM, MSc, PhD; Ressler, Kerry J. MD, PhD; Conneely, Karen N. PhD; Sotoodehnia, Nona MD, MPH; Kardia, Sharon L. R. PhD; Melzer, David MBBCh, PhD; Baccarelli, Andrea A. MD, PhD; van Meurs, Joyce B. J. PhD; Romieu, Isabelle MD, ScD; Arnett, Donna K. PhD; Ong, Ken K. MB BChir, PhD; Liu, Yongmei MD, PhD; Waldenberger, Melanie PhD; Deary, Ian J. PhD; Fornage, Myriam PhD; Levy, Daniel MD; London, Stephanie J. MD, DrPH
Circulation: Cardiovascular Genetics.
9(5):436-447, October 2016.
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Background-: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders.
Methods and Results-: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1x10-7 (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1x10-7 (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs.
Conclusions-: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.
(C) 2016 American Heart Association, Inc.