Genetics, Dyslipidemia, and Cardiovascular Disease: New Insights

The cardiovascular (CV) risk related to lipid disorders is well established and is based on a robust body of evidence from well-designed randomized clinical trials, as well as prospective observational studies. In the last two decades, significant advances have been made in understanding the genetic basis of dyslipidemias. The present review is intended as a comprehensive discussion of current knowledge about the genetics and pathophysiology of disorders that predispose to dyslipidemia. We also focus on issues related to statins and the proprotein convertase subtilisin/kexin type 9 (PCSK9) and some of its polymorphisms, as well as new cholesterol-lowering medications, including PCSK9 inhibitors.

Cholesterol is essential for the proper functioning of several body systems. However, dyslipidemia-especially elevated low-density lipoprotein (LDL-c) and triglyceride levels, as well as reduced lipoprotein lipase activity-is associated with an increased risk of coronary artery disease (CAD). High-density lipoprotein (HDL-c), however, seems to play a role as a risk marker rather than as a causal factor of the disease, as suggested by Mendelian randomization studies. Several polymorphisms in the lipoprotein lipase locus have been described and are associated with variations in the activity of this enzyme, producing high concentrations of triglycerides and increased risk of CAD. Dyslipidemia, especially increased LDL-c and triglyceride levels, continues to play a significant role in CV risk. The combination of genetic testing and counseling is important in the management of patients with dyslipidemia of genetic etiology. Strategies focused on primary prevention can offer an opportunity to reduce CV events.