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      Epigenetic Signatures of Cigarette Smoking

      research-article
      , PhD 1 , 2 , , PhD 3 , , PhD 4 , 5 , 6 , , PhD 7 , , PhD 8 , , MS 9 , 10 , , PhD 11 , , PhD 12 , , PhD 13 , , PhD 14 , , ScD 15 , 16 , , PhD, MPH 17 , , BA 18 , , PhD 19 , , MPH 20 , , PhD 21 , , PhD 12 , , PhD 6 , 22 , , PhD 6 , 22 , , MStat 23 , , MS 14 , , PhD 24 , , MD, PhD 25 , , PhD 17 , , PhD 20 , , PhD 26 , , MS 26 , , PhD 2 , , PhD 2 ,   , MD 2 , 27 , , PhD 2 , , MD, MPH 1 , , PhD 12 , , PhD 12 , , PhD 4 , 6 , 22 , , PhD 6 , , PhD 4 , 28 , , PhD 29 , , MD, MPH 8 , , PhD 13 , , PhD 14 , , PhD 30 , , PhD 31 , , MD 32 , 33 , , PhD, MPH, FFPH 16 , , PhD 9 , , MD, PhD 34 , , PhD 35 , , PhD 35 , , MD, PhD 36 , , MD 37 , , PhD 38 , , PhD 38 , , MD 39 , , MD 40 , , PhD, MPH 17 , 41 , , PhD 42 , , MD 43 , 44 , , MD, PhD 43 , 45 , , MD, PhD 18 , 47 , , PhD 47 , 48 , 49 , , MD 50 , , MPP 18 , , PhD 51 , , MD, MPH 52 , , MD, MS 53 , , DVM, MSc, PhD 16 , , MD, PhD 42 , 44 , 54 , , PhD 55 , , MD, MPH 56 , , PhD 17 , , MBBCh, PhD 7 , , MD, PhD 35 , 57 , , PhD 9 , , MD, ScD 16 , , PhD 14 , , MB BChir, PhD 13 , , MD, PhD 8 , , PhD 12 , , PhD 4 , 58 , , PhD 26 , , MD 2 , , MD, DrPH 60
      Circulation. Cardiovascular genetics
      epigenetics, smoking, biomarker, Genome Wide Association Study, meta-analysis, methylation

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          Abstract

          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 2,433 current, 6,518 former, and 6,956 never smokers). Comparing current versus never smokers, 2,623 CpG sites (CpGs), annotated to 1,405 genes, were statistically significantly differentially methylated at Bonferroni threshold of p<1×10 −7 (18,760 CpGs at False Discovery Rate (FDR)<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<1×10 −7 (2,623 CpGs at FDR<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 biologic 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.

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          Author and article information

          Journal
          101489144
          35623
          Circ Cardiovasc Genet
          Circ Cardiovasc Genet
          Circulation. Cardiovascular genetics
          1942-325X
          1942-3268
          3 October 2016
          20 September 2016
          October 2016
          01 October 2017
          : 9
          : 5
          : 436-447
          Affiliations
          [1 ]Inst for Aging Research, Hebrew SeniorLife, Dept of Medicine Beth Israel Deaconess Medical Center & Harvard Medical School, Boston
          [2 ]Population Sciences Branch, National Heart, Lung, and Blood Inst, National Insts of Health, Bethesda, MD & Framingham Heart Study, Framingham, MA
          [3 ]Dept of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
          [4 ]Centre for Cognitive Ageing & Cognitive Epidemiology, Edinburgh, UK
          [5 ]Centre for Genomic & Experimental Medicine, Inst of Genetics & Molecular Medicine, Univ of Edinburgh, Edinburgh, UK
          [6 ]Queensland Brain Inst, Univ of Queensland, Brisbane, Australia
          [7 ]Epidemiology & Public Health Group, Inst of Biomedical & Clinical Science, Univ of Exeter Medical School, Exeter, UK
          [8 ]Dept of Epidemiology & Prevention, Public Health Sciences, Winston-Salem, NC
          [9 ]Dept of Internal Medicine, Erasmus Univ Medical Center, Rotterdam, the Netherlands
          [10 ]Dept of Clinical Chemistry, Erasmus Univ Medical Center, Rotterdam, the Netherlands
          [11 ]Division of Biostatistics, Univ of Minnesota, Minneapolis, MN
          [12 ]Research Unit of Molecular Epidemiology, Inst of Epidemiology II, Helmhotz Zentrum Muenchen, Munich, Germany
          [13 ]MRC Epidemiology Unit, Inst of Metabolic Science, Univ of Cambridge, Cambridge, UK
          [14 ]Dept of Epidemiology, Univ of Alabama at Birmingham, Birmingham, AL
          [15 ]Autonomous Metropolitan Univ-Iztapalapa, Mexico City, Mexico
          [16 ]International Agency for Research on Cancer (IARC), Lyon, France
          [17 ]Dept of Epidemiology, School of Public Health, Univ of Michigan, Ann Arbor, MI
          [18 ]Cardiovascular Health Research Unit, Dept of Medicine, Epidemiology, & Health Services, Univ of Washington, Seattle, WA
          [19 ]Dept of Environmental Health, Rollins School of Public Health, Emory Univ, Atlanta, GA
          [20 ]School of Public Health, Univ of California, Berkeley, CA
          [21 ]Division of Epidemiology & Community Health, School of Public Health, Univ of Minnesota, Minneapolis, MN
          [22 ]Univ of Queensland Diamantina Inst, Translational Research Inst, Univ of Queensland, Brisbane, Australia
          [23 ]Dept of Biostatistical Sciences, Division of Public Health Sciences, Winston-Salem, NC
          [24 ]HudsonAlpha Inst for Biotechnology, Huntsville, AL
          [25 ]Clinical Research Branch, National Inst on Aging, Baltimore, MD
          [26 ]Human Genetics Center, School of Public Health, The Univ of Texas Health Science Center at Houston, Houston, TX
          [27 ]Children's Hospital, Boston, MA
          [28 ]Alzheimer Scotland Dementia Research Centre, Univ of Edinburgh, Edinburgh, UK
          [29 ]Dept of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC
          [30 ]School of Biomedical Informatics & School of Public Health, The Univ of Texas Health Science Center at Houston, Houston, TX
          [31 ]Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany
          [32 ]MRC/PHE Centre for Environment & Health, School of Public Health, Imperial College London, UK
          [33 ]HuGeF Foundation, Torino, Italy
          [34 ]Dept of Epidemiology, Erasmus Univ Medical Center, Rotterdam, The Netherlands
          [35 ]Dept of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA
          [36 ]Dept of Preventive Medicine and the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern Univ, Chicago, IL
          [37 ]VA Normative Aging Study, VA Boston Healthcare System & Dept of Medicine, Boston Univ School of Medicine, Boston, MA
          [38 ]Laboratory of Neurogenetics, National Inst on Aging, National Insts of Health, Bethesda, MD
          [39 ]Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy
          [40 ]Division of Nephrology & Hypertension, Mayo Clinic, Rochester, MN
          [41 ]Research Center for Group Dynamics, Inst for Social Research, Univ of Michigan, Ann Arbor, MI
          [42 ]Psychiatry & Behavioral Sciences, Emory Univ School of Medicine, Atlanta, GA
          [43 ]Dept of Translational Research in Psychiatry, Max-Planck Inst of Psychiatry, Munich, Germany
          [44 ]Division of Depression & Anxiety Disorders, McLean Hospital, Belmont, MA
          [45 ]Dept of Psychiatry and Behavioral Sciences, Emory Univ School of Medicine, Atlanta, GA
          [46 ]Group Health Research Inst, Group Health Cooperative, Seattle, WA
          [47 ]Inst for Translational Genomics & Population Sciences, Los Angeles BioMedical Research Inst
          [48 ]Division of Genomic Outcomes, Dept of Pediatrics, Harbor-UCLA Medical Center, Torrance
          [49 ]Depts of Pediatrics, Medicine, and Human Genetics, UCLA, Los Angeles, CA
          [50 ]Center for Lung Biology, Division of Pulmonary & Critical Care Medicine, Dept of Medicine, Univ of Washington, Seattle, WA
          [51 ]Harvard School of Public Health
          [52 ]Channing Division of Network Medicine, Brigham & Women's Hospital, Harvard Medical School
          [53 ]Boston Univ School of Medicine
          [54 ]Dept of Psychiatry, Harvard Medical School
          [55 ]Dept of Human Genetics, Emory Univ School of Medicine, Atlanta, GA
          [56 ]Cardiovascular Health Research Unit, Division of Cardiology, Dept of Epidemiology, Univ of Washington, Seattle, WA
          [57 ]Dept of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA
          [58 ]Dept of Psychology, Univ of Edinburgh, Edinburgh, UK
          [60 ]Epidemiology Branch, National Inst of Environmental Health Sciences, National Insts of Health, Dept of Health and Human Services, Research Triangle Park, NC
          Author notes
          Correspondence: Stephanie J. London, MD, DrPH, NIEHS, NIH, Epidemiology Branch, PO Box 12233, Rm A306, Research Triangle Park, NC 27709, Tel: 919-541-5772, Fax: 301-480-3290, london2@ 123456niehs.nih.gov
          [*]

          contributed equally as first authors

          [**]

          senior authors

          Article
          PMC5267325 PMC5267325 5267325 nihpa817273
          10.1161/CIRCGENETICS.116.001506
          5267325
          27651444
          0c6c05e0-aaee-44a1-94de-acd0076facb8
          History
          Categories
          Article

          epigenetics,smoking,biomarker,Genome Wide Association Study,meta-analysis,methylation

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