Abstract
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 metaanalysis 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.
| Original language | English |
|---|---|
| Pages (from-to) | 4611-4623 |
| Number of pages | 13 |
| Journal | Human Molecular Genetics |
| Volume | 25 |
| Issue number | 21 |
| DOIs | |
| Publication status | Published - 1 Nov 2016 |
Bibliographical note
Funding Information:The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. The authors are grateful to the study participants, the staff from FHS, InCHIANTI, RS, SHIP, KORA and EGCUT studies, and the participating general practitioners and pharmacists. Furthermore, we thank Marjolein Peters, MSc, Ms. Mila Jhamai, Ms. Jeannette M. Vergeer-Drop, Ms. Bernadette van Ast-Copier, Mr. Marijn Verkerk and Jeroen van Rooij, BSc for their help in creating the RNA array expression database in RS. We are grateful to the field staff in Augsburg and Munich who were involved in the conduct of the KORA studies, and the staff of the Genome Analysis Center at the Helmholtz ZentrumMünchen involved in the omics measurements. The Framingham Heart Study is funded by the National Institutes of Health contract N01-HC-25195 HHSN268201500001I; 1RO1 HL64753; R01 HL076784; 1 R01 AG028321; Dr. Benjamin is funded by 1P50HL120163. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, National Institutes of Health, Bethesda, MD. The InCHIANTI study was supported as a "targeted project" (ICS110.1/RF97.71) by the Italian Ministry of Health at baseline (1998-2000), with subsequent visits supported in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of RNA-expression array data for the Rotterdam Study was executed and funded by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. We thank Marjolein Peters, MSc, Ms. Mila Jhamai, Ms. Jeannette M. Vergeer-Drop, Ms. Bernadette van Ast-Copier, Mr. Marijn Verkerk and Jeroen van Rooij, BSc for their help in creating the RNA array expression database. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network 'Greifswald Approach to Individualized Medicine (GANI_MED)' funded by the grant 03IS2061A of the Federal Ministry of Education and Research. Generation of whole-blood transcriptome data was funded by the grant no. 03ZIK012 of the Federal Ministry of Education and Research. The University of Greifswald is a member of the Caché Campus program of the InterSystems GmbH. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum München-German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The German Diabetes Center is funded by the German Federal Ministry of Health (BMG) and the Ministry of Innovation, Science, Research and Technology (MIWF) of the State North Rhine-Westphalia. This study was supported in part by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.). We are indebted to all study participants. Furthermore, we are grateful to the field staff in Augsburg and Munich who were involved in the conduct of the KORA studies, and the staff of the Genome Analysis Center at the Helmholtz Zentrum München involved in the omics measurements. EGCUT work was supported through the Estonian Genome Center of University of Tartu by the Targeted Financing from the Estonian Ministry of Science and Education [SF0180142s08]; the Development Fund of the University of Tartu (grant SP1GVARENG); the European Regional Development Fund to the Centre of Excellence in Genomics (EXCEGEN; grant 3.2.0304.11-0312); and through FP7 grant 313010.
Publisher Copyright:
© The Author 2016. Published by Oxford University Press.