Cardiovascular diseases (CVD) are major threats to the modern societies. The high burden of CVD is attributable to the increasing incidence of atherosclerosis. Activation of immune cells (including monocytes) by pathological factors (i.e. obesity, hypercholesterolemia and hyperglycaemia) in the vascular intima serves as the key mechanism to promote atherosclerosis progression. Moreover, such immunological activation exhibits ‘memories’ which cause disease relapse and drug resistance in mouse models. Accumulating evidence has proved the crucial involvement of drug-targetable epigenome events in the atherogenic monocyte activation and inflammatory memory. Despite this recognition, there has been a major gap to understand how the monocyte epigenome remodeling in patients with high CVD risks may influence or even predict the clinical outcomes, because most of the current studies from top laboratories are mainly based on mice. While the key epigenome regulatory mechanisms remain species conserved, the precise genome location and the composition of genomic regulatory regions and networks are substantially different, making the translation into human diseases challenging. In collaboration with the clinical doctors and scientists, we propose to apply our well-established pre-clinical epigenome analytical techniques in a large and well characterized Swedish cohort of patients with lipid disorders to understand how an excess of lipids in circulation alters monocyte epigenome and manipulates their metabolic activation, memory and atherogenic properties, and thereby influences atherosclerosis development in humans.