The availability of DNA methylation and mRNA expression data from the same samples is a major strength of this study. Therefore, we were able to conduct an in-depth exploration of the association between smoking, DNA methylation and mRNA expression of CAD-related genes. Our study involved methylation and expression data from whole blood samples and not from vascular or lung tissue. This could be a limitation, since methylation and expression might be tissue specific. However, the relationship between smoking and DNA methylation has been confirmed in other tissues including lung tissue [20]. Furthermore, in a study of atherosclerotic tissue, three of our identified genes (PRKCZ, LCCR2 and SMG6) were found to be differentially methylated [21]. This provides further evidence that our findings may be influential in the atherosclerotic pathway. However, this needs further investigation in functional studies. A second limitation is the challenge of gene annotation in GWAS. GWAS locate risk variants for the phenotype under study, but the underlying causal gene might be difficult to designate. To minimize this problem, we limited our analysis to in-gene variants and variants with
