Coagulation factor VII (FVII) is a clotting protein which triggers thrombus formation in the arterial vessels and modulates coronary artery disease (CAD) risk. Plasma FVII concentrations are largely determined by genetic markers as the A2 allele causing lower FVIIa and reduced CAD risk, or the -402A allele that induces higher FVIIa. Other mechanisms such as DNA methylation regulate gene expression via epigenetic phenomena. The epigenetic regulation through methylation at F7 promoter as well as the inter-relationship of genetic and epigenetic modifications at F7 promoter site were both previously unexplored. F7 epigenetic regulation through methylation relates to CAD risk by affecting plasma FVIIa concentrations and its role prevails in those A1A1 subjects, i.e. not carriers of the functional A2 allele. The correlation between a polymorphism and its effect on DNA methylation and, consequently, on gene product regulation is a novel and very intriguing concept. The striking impact of the findings pertains also to the fact that, differently form genetic marks, epigenetic transcriptional regulation systems are potentially reversible, therefore opening up possible fascinating genetic-epigenetic approaches for future preventive strategies. (Dr Simonetta Friso, http://jmg.bmj.com/content/49/3/192 )