Atherosclerotic cardiovascular disease secondary to deposition of apolipoprotein B-containing lipoproteins in the artery wall is a leading cause of mortality. Therapies that reduce serum levels of atherogenic lipoprotein-cholesterol have been successful in reducing cardiovascular mortality, but this approach requires long-term treatment and substantial residual risk remains. Here, we investigate mechanistic determinants of atherosclerosis protection by two potential therapeutic approaches for lowering of residual cardiovascular risk. Using mouse models, we show that the nuclear receptor liver X receptor exerts an anti-inflammatory activity on innate immunity and atherosclerosis through both promotion of cholesterol efflux and a direct cis-repressive activity affecting neutrophil inflammation. We then assess the causal role of the cholesterol efflux pathway in human cardiovascular events by using genetic variants that modify high density lipoprotein-cholesterol in instrumental variable analysis.

We show that this pathway is associated with protection from cardiovascular disease in a precise and robust Mendelian randomization analysis on an FDR-controlled set of variants, which suggests a causal effect. Thus, agents that target the cholesterol efflux and liver X receptor cis-repression pathways may be protective in atherosclerosis.