Translational Medicine in Atherosclerosis: From Human Genetics to New Biology to Novel Therapeutics

Abstract

Despite advances over the last few decades, atherosclerotic cardiovascular disease (ASCVD) remains a major public health issue worldwide. New therapies for the prevention and treatment of ASCVD are still needed. The investigation of monogenic disorders, such as those associated with extremes of plasma lipids, have yielded new therapeutic targets and spurred the development of new therapeutic approaches. Unbiased genome-wide studies have identified a large number of novel genetic loci associated with different manifestations of ASCVD (eg. myocardial infarction and obstructive CAD) as well as risk factor traits (eg. plasma lipids). These discoveries are beginning to result in new insights into biology and physiology relevant to the development of ASCVD. For example, a locus on chromosome 1p13 was found to be significantly associated with MI, as well as noted to be one the strongest loci in the genome associated with LDL cholesterol. The causal gene at this locus, SORT1, encodes a protein sortilin that through action in the liver has important effects on LDL metabolism. Several other loci associated with plasma lipid traits have yielded new insights into the regulation of lipoprotein metabolism. Similarly, loci associated with MI and CAD are putting new molecules on the map that causally influence the development of atherosclerosis or plaque disruption. Just as the study of monogenic disorders has yielded new therapeutic targets, it is expected that translation of the new biology unfolding as a result of genome-wide studies of ASCVD and its risk factors will ultimately yield novel therapies for the treatment of atherosclerotic disease.