The Genetic Basis of Hypertriglyceridemia

Abstract

Purpose of review: Hypertriglyceridemia is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. Severe hypertriglyceridemia may sometimes be a monogenic condition. However, in the vast majority of patients, hypertriglyceridemia is due to the cumulative effect of multiple genetic risk variants along with lifestyle factors, medications, and disease conditions that elevate triglyceride levels. In this review, we will summarize recent progress in the understanding of the genetic basis of hypertriglyceridemia.

Recent findings: More than 300 genetic loci have been identified for association with triglyceride levels in large genome-wide association studies. Studies combining the loci into polygenic scores have demonstrated that some hypertriglyceridemia phenotypes previously attributed to monogenic inheritance have a polygenic basis. The new genetic discoveries have opened avenues for the development of more effective triglyceride-lowering treatments and raised interest towards genetic screening and tailored treatments against hypertriglyceridemia. The discovery of multiple genetic loci associated with elevated triglyceride levels has led to improved understanding of the genetic basis of hypertriglyceridemia and opened new translational opportunities.

Keywords: Dyslipidemia; Genetic variant; Human genetics; Hypertriglyceridemia; Monogenic; Polygenic; Triglycerides.

Fig. 1

Genetic mechanisms implicated in hypertriglyceridemia. A Dietary triglycerides are absorbed from the small intestine and enter the circulation packed in chylomicrons. The liver synthesizes triglycerides de novo from free fatty acids and packs them into very low-density lipoproteins (VLDLs). B The chylomicrons and VLDL deliver the triglycerides to adipose tissue, skeletal muscle, and cardiac muscle where lipoprotein lipase (LPL) cleaves triglycerides. C In the adipose tissue, triglycerides are stored within adipocyte lipid droplets. D The breakdown of triglycerides by LPL turns chylomicrons and VLDL gradually into remnant lipoproteins (RPLs). E Remnant lipoproteins are cleared by the liver via ApoE that facilitates binding of RLP to the LDL receptor (LDLR) on the liver. When RPL levels are high, RLP clearance by the liver reaches saturation and RLP molecules accumulate in plasma. Figure icons were created with BioRender.com

Fig. 2

The genetic architecture of hypertriglyceridemia. In very rare, monogenic disorders, a single recessive variant may cause a severe hypertriglyceridemia (red box). Rare heterozygous variants with large effects may contribute to the clustering of certain hypertriglyceridemia phenotypes in families (yellow box). In most cases of hypertriglyceridemia, the genetic basis is highly polygenic, driven by the cumulative effect of multiple common and rare variants with modest effect sizes (green box)