A whole-blood transcriptome meta-analysis identifies gene expression signatures of cigarette smoking.
Cigarette smoking is a leading modifiable cause of death worldwide. We hypothesized that cigarette smoking induces extensive transcriptomic changes that lead to target-organ damage and smoking-related diseases. We performed a meta-analysis of transcriptome-wide gene expression using whole blood-derived RNA from 10,233 participants of European ancestry in six cohorts (including 1421 current and 3955 former smokers) to identify associations between smoking and altered gene expression levels. At a false discovery rate (FDR) <0.1, we identified 1270 differentially expressed genes in current vs. never smokers, and 39 genes in former vs. never smokers. Expression levels of 12 genes remained elevated up to 30 years after smoking cessation, suggesting that the molecular consequence of smoking may persist for decades. Gene ontology analysis revealed enrichment of smoking-related genes for activation of platelets and lymphocytes, immune response, and apoptosis. Many of the top smoking-related differentially expressed genes, including LRRN3 and GPR15, have DNA methylation loci in promoter regions that were recently reported to be hypomethylated among smokers. By linking differential gene expression with smoking-related disease phenotypes, we demonstrated that stroke and pulmonary function show enrichment for smoking-related gene expression signatures. Mediation analysis revealed the expression of several genes (e.g. ALAS2) to be putative mediators of the associations between smoking and inflammatory biomarkers (IL6 and C-reactive protein levels). Our transcriptomic study provides potential insights into the effects of cigarette smoking on gene expression in whole blood and their relations to smoking-related diseases. The results of such analyses may highlight attractive targets for treating or preventing smoking-related health effects.
Boston University’s Framingham Heart Study, Framingham, MA, USA.|The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
Tianxiao
T
Huan
Boston University’s Framingham Heart Study, Framingham, MA, USA.|The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.|Hebrew SeniorLife, Harvard Medical School, Boston, MA, USA.
Roby
R
Joehanes
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.|Genetics of Obesity & Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Claudia
C
Schurmann
Institute of Human Genetics, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Human Genetics, Technical University Munich, Munich, Germany.
Katharina
K
Schramm
Epidemiology and Public Health Group, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
Luke C
LC
Pilling
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.|The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands.
Marjolein J
MJ
Peters
The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands.
Reedik
R
Mägi
Harvard Medical School, Boston, MA, USA.
Dawn
D
DeMeo
Boston University School of Medicine and School of Public Health, Boston, MA, USA.
George T
GT
O'Connor
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
Luigi
L
Ferrucci
Institute for Community Medicine, University of Greifswald, Greifswald, Germany.
Alexander
A
Teumer
Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Georg
G
Homuth
Department of Prosthetic Dentistry, Gerostomatology and Dental Materials, Center of Oral Health, University Medicine Greifswald, Greifswald, Germany.
Reiner
R
Biffar
Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Uwe
U
Völker
Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
Christian
C
Herder
Research Unit of Molecular Epidemiology, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
Melanie
M
Waldenberger
Research Unit of Molecular Epidemiology, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Epidemiology II, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
Annette
A
Peters
Institute of Epidemiology II, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
Sonja
S
Zeilinger
The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands.|The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands.|The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands.
Andres
A
Metspalu
The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus Medical Center Rotterdam, The Netherlands.
Albert
A
Hofman
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.|The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus Medical Center Rotterdam, The Netherlands.
André G
AG
Uitterlinden
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Dena G
DG
Hernandez
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Andrew B
AB
Singleton
Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy.
Stefania
S
Bandinelli
Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, MD, USA.
Peter J
PJ
Munson
Boston University School of Medicine and School of Public Health, Boston, MA, USA.
Honghuang
H
Lin
Boston University’s Framingham Heart Study, Framingham, MA, USA.|The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands.|The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands.|Boston University School of Medicine and School of Public Health, Boston, MA, USA.|The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands.
Emelia J
EJ
Benjamin
The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands.|Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Tõnu
T
Esko
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.|German Center for Neurodegenerative Diseases DZNE, Site Rostock/Greifswald, Germany.
Hans J
HJ
Grabe
Institute of Human Genetics, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Human Genetics, Technical University Munich, Munich, Germany.
Holger
H
Prokisch
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.|The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden/Rotterdam, The Netherlands.
Joyce B J
JB
van Meurs
Epidemiology and Public Health Group, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
David
D
Melzer
Boston University’s Framingham Heart Study, Framingham, MA, USA.|The Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
Daniel
D
Levy
D000328:Adult; D000368:Aged; D000073865:Cigarette Smoking / Q000097:blood / Q000235:genetics*; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D012907:Smoking / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects; D044465:White People / Q000235:genetics