Genomics of hypertriglyceridemia

With regard to heritability of phenotypes, the serum triglyceride level is considered to be highly heritable, with approximately 50% of its variability estimated to derive from parents. Thus, approximately 50% could be modifiable via environmental factors, including lifestyle and medications. Lipoproteins are definitive risk factors for atherosclerotic cardiovascular disease (ASCVD); among these, low-density lipoprotein (LDL) particles have been established as a causal factor for the development of ASCVD. Recently, triglyceride-rich lipoproteins have emerged as additional lipoproteins, which should be considered as residual targets for ASCVD risk reduction by LDL-lowering therapies. Compared with LDL particles, triglyceride-rich lipoproteins are significantly increased in the postprandial state, making it difficult to assess their clinical relevance. However, numerous pieces of evidence suggest that fasting and non-fasting triglycerides are associated with ASCVD. In addition, a recent meta-analysis of a Mendelian randomization study suggests that consideration of apolipoprotein B (APOB) might be better than considering LDL and triglyceride-rich lipoproteins separately. In this review, we examine (1) how triglyceride levels are determined by genetics, (2) lessons from extreme cases exhibiting severe hypertriglyceridemia, and (3) why triglycerides are important, by highlighting clinical and genetic evidence of their associations with ASCVD risk.