Smoking is Associated to DNA Methylation in Atherosclerotic Carotid Lesions

Marten A Siemelink, Sander W van der Laan, Saskia Haitjema, Ian D van Koeverden, Jacco Schaap, Marian Wesseling, Saskia C A de Jager, Michal Mokry, Maarten van Iterson, Koen F Dekkers, René Luijk, Hassan Foroughi Asl, Tom Michoel, Johan L M Björkegren, Einari Aavik, Seppo Ylä-Herttuala, Gert J de Borst, Folkert W Asselbergs, Hamid El Azzouzi, Hester M den RuijterBas T Heijmans, Gerard Pasterkamp

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)e002030
JournalCirculation: Genomic and Precision Medicine
Issue number9
Publication statusPublished - 17 Sept 2018


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