Journal
CIRCULATION-GENOMIC AND PRECISION MEDICINE
Volume 11, Issue 9, Pages -Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGEN.117.002030
Keywords
atherosclerosis; ardiovascular disease; DNA methylation; quantitative trait loci; smoking; tobacco
Funding
- European Union (BiomarCaRE) [HEALTH-2011-278913]
- technology foundation Stichting voor de Technische Wetenschappen - Danone partnership program [11679]
- Netherlands CardioVascular Research Initiative of the Netherlands Heart Foundation [CVON 2011/B019, CVON 2017-20]
- Inter-university Cardiology Institute of the Netherlands [09.001]
- FP7 European Union project CVgenes@target [HEALTH-F2-2013-601456]
- University College London Hospitals' Biomedical Research Centre
- Dutch Heart Foundation [2014T001]
- Netherlands Heart Foundation [2017T075]
- PRecOcious Coronary ARtery DISease (PROCARDIS) in the sixth European Union-framework program [LSHM-CT-2007-037273]
- Swedish Heart-Lung Foundation
- King Gustaf V and Queen Victoria's Foundation of Freemasons
- Swedish Society of Medicine
- University of Tartu
- Estonian Research Council Estonian Research Information System [ETIS]
- Biotechnology and Biological Sciences Research Council
- Clinical Gene Networks AB
- Academy of Finland
- University of Eastern Finland spearhead program
- Kuopio University Hospital
- Sigrid Juselius Foundation
Ask authors/readers for more resources
BACKGROUND: Tobacco smoking is a major risk factor for atherosclerotic disease and has been associated with DNA methylation (DNAm) changes in blood cells. However, whether smoking influences DNAm in the diseased vascular wall is unknown but may prove crucial in understanding the pathophysiology of atherosclerosis. In this study, we associated current tobacco smoking to epigenome-wide DNAm in atherosclerotic plaques from patients undergoing carotid endarterectomy. METHODS: DNAm at commonly methylated sites (cytosine-guanine nucleotide pairs separated by a phospho-group [CpGs]) was assessed in atherosclerotic plaque samples and peripheral blood samples from 485 carotid endarterectomy patients. We tested the association of current tobacco smoking with DNAm corrected for age and sex. To control for bias and inflation because of cellular heterogeneity, we applied a Bayesian method to estimate an empirical null distribution as implemented by the R package bacon. Replication of the smoking-associated methylated CpGs in atherosclerotic plaques was executed in the second sample of 190 carotid endarterectomy patients, and results were meta-analyzed using a fixed-effects model. RESULTS: Tobacco smoking was significantly associated to differential DNAm in atherosclerotic lesions of 4 CpGs (false discovery rate <0.05) mapped to 2 different genes (AHRR, ITPK1) and 17 CpGs mapped to 8 genes and RNAs in blood. The strongest associations were found for CpGs mapped to the gene AHRR, a repressor of the aryl hydrocarbon receptor transcription factor involved in xenobiotic detoxification. One of these methylated CpGs were found to be regulated by local genetic variation. CONCLUSIONS: The risk factor tobacco smoking associates with DNAm at multiple loci in carotid atherosclerotic lesions. These observations support further investigation of the relationship between risk factors and epigenetic regulation in atherosclerotic disease.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available