title: Tobacco smoking is associated with methylation of genes related to coronary artery disease.
abstract: BACKGROUND
  Tobacco smoking, a risk factor for coronary artery disease (CAD), is known to modify DNA methylation. We hypothesized that tobacco smoking modifies methylation of the genes identified for CAD by genome-wide association study (GWAS).
  
  
  RESULTS
  We selected genomic regions based on 150 single-nucleotide polymorphisms (SNPs) identified in the largest GWAS on CAD. We investigated the association between current smoking and the CpG sites within and near these CAD-related genes. Methylation was measured with the Illumina Human Methylation 450K array in whole blood of 724 Caucasian subjects from the Rotterdam Study, a Dutch population based cohort study. A total of 3669 CpG sites within 169 CAD-related genes were studied for association with current compared to never smoking. Fifteen CpG sites were significantly associated after correction for multiple testing (Bonferroni-corrected p value <1.4 × 10(-5)). These sites were located in the genes TERT, SARS, GNGT2, SMG6, SKI, TOM1L2, SIPA1, MRAS, CDKN1A, LRRC2, FES and RPH3A. In 12 sites, current smoking was associated with a 1.2 to 2.4 % lower methylation compared to never smoking; and in three sites, it was associated with a 1.2 to 1.8 % higher methylation. The effect estimates were lower in 10 of the 15 CpG sites when comparing current to former smoking. One CpG site, cg05603985 (SKI), was found to be associated with expression of nearby CAD-related gene PRKCZ.
  
  
  CONCLUSIONS
  Our study suggests an effect of tobacco smoking on DNA methylation of CAD-related genes and thus provides novel insights in the pathways that link tobacco smoking to risk of CAD.
authors.affiliation: Department of Epidemiology, Erasmus University Medical Centre, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands ; Netherlands Institute for Health Sciences, Erasmus University Medical Centre, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Rebecca V
authors.initials: RV
authors.lastname: Steenaard
authors.affiliation: Department of Epidemiology, Erasmus University Medical Centre, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Symen
authors.initials: S
authors.lastname: Ligthart
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Centre, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Lisette
authors.initials: L
authors.lastname: Stolk
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Centre, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands ; The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Einthovenweg 20, 2333 ZC Leiden/ 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Marjolein J
authors.initials: MJ
authors.lastname: Peters
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Centre, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Joyce B
authors.initials: JB
authors.lastname: van Meurs
authors.affiliation: Department of Epidemiology, Erasmus University Medical Centre, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands ; Department of Internal Medicine, Erasmus University Medical Centre, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands ; The Netherlands Genomics Initiative-sponsored Netherlands Consortium for Healthy Aging (NGI-NCHA), Einthovenweg 20, 2333 ZC Leiden/ 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Epidemiology, Erasmus University Medical Centre, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Epidemiology, Erasmus University Medical Centre, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
authors.affiliation: Department of Epidemiology, Erasmus University Medical Centre, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
keywords: Coronary artery disease; DNA methylation; Tobacco smoking; White blood cells; mRNA expression