Genetics of hypertriglyceridemia and atherosclerosis

The relationship between elevated triglyceride levels (i.e. hypertriglyceridemia) and risk of atherosclerotic cardiovascular disease (ASCVD) has been investigated for decades. Recent genetic studies have sought to resolve the decades-old question of a causal relationship.

Genetic studies seem to demonstrate associations between elevated triglyceride levels and ASCVD risk. Mendelian randomization studies suggest this association may be causal. However, simultaneous pleiotropic effects of metabolically linked lipid variables - such as non-HDL cholesterol, apolipoprotein B and HDL cholesterol -- often go unaccounted for in these studies. Complex underlying pleiotropic interactions of triglycerides with these lipid fractions together with unmeasured intercalated nonlipid-related mechanisms, such as inflammation and coagulation, impair the ability of genetic studies to implicate a direct role for triglycerides on ASCVD risk. One potential mechanism seems largely driven by the cholesterol carried within triglyceride-rich lipoproteins and their remnants, rather than their triglyceride content.

Although the exact mechanisms linking elevated triglyceride levels to ASCVD remain to be determined, new therapeutics that reduce triglyceride levels might be advantageous in certain patients. Newer investigational triglyceride-lowering therapies derived from human genetics target key proteins, such as apo C-III and ANGPTL3. Although these treatments clearly lower triglyceride levels, their efficacy in atherosclerotic risk reduction remains unproven.