Are Toll-like receptors potential drug targets for atherosclerosis? Evidence from genetic studies to date

Low-density lipoprotein cholesterol lowering, most notably via statin therapy, has successfully reduced the burden of coronary artery disease (CAD) in recent decades. However, the residual risk remaining even after aggressive lipid lowering has renewed interest in alternative targets. Anti-inflammatory drugs are thought to have much potential in this context, but side effects associated with long-term use of conventional anti-inflammatories, such as NSAIDs and glucocorticoids, preclude their use as preventive agents for CAD. Evidence from epidemiological studies and murine models of atherosclerosis suggests that Toll-like receptors (TLRs) may have utility as targets for more focused anti-inflammatories, but it remains unclear if this pathway is causally related to CAD in man. Here, we review recent insight into this question gained from genetic studies of cardiovascular risk and innate immune function, focussing on the potential of Mendelian randomisation approaches based on intracellular-signalling pathways to identify and prioritise targets for drug development.