Genetics of Hypertriglyceridemia

Figure 1. Population distribution of plasma TG levels. The distribution of TG levels has a positive (right) skew in the general population. In this review, normal TG levels are considered as <2.0 mmol/L (175 mg/dL), while anything above normal can be classified as hypertriglyceridemia. “Mild-to-moderate” hypertriglyceridemia is defined as 2.0–9.9 mmol/L (175–885 mg/dL), while “severe” hypertriglyceridemia is defined as ≥10.0 mmol/L (≥885 mg/dL). Severe hypertriglyceridemia can be further defined as FCS or MCM, depending on its genetic basis. The black dashed lines indicate the 75th percentile (2.0 mmol/L), 95th percentile (3.0 mmol/L), and 99th percentile (5.0 mmol/L) for TG levels. FCS, familial chylomicronemia syndrome; MCM, multifactorial chylomicronemia; TG, triglyceride.

Figure 2. Overview of TG metabolism focusing on human disease genes. TG-rich lipoprotein assembly requires TG synthesis from fatty acids (FA) in the intestine or liver using tissue-specific isoforms of diacylglycerol acyltransferase (DGAT). Microsomal triglyceride transfer protein (MTP) fuses TG, cholesterol and phospholipids, with tissue-specific isoforms of apolipoprotein (apo) B: intestinal B-48 to form chylomicrons and hepatic B-100 to form very-low density lipoprotein (VLDL). Chylomicrons enter plasma through the thoracic duct while the liver secretes VLDL directly into the bloodstream. Lipoprotein lipase (LPL) is the key enzyme for hydrolysis of both circulating chylomicrons and VLDL, producing chylomicron remnants and intermediate-density lipoprotein (IDL) particles, respectively. Chylomicron remnant and IDL clearance by the liver is mediated by apo E (not shown). IDL is further hydrolyzed by hepatic lipase (HL) to generate low-density lipoprotein (LDL), which is cleared by the LDL receptor (LDLR), regulated in part by proprotein convertase subtilisin kexin 9 (PCSK9). Lipase maturation factor 1 (LMF1) chaperones LPL prior to secretion from adipocytes or myocytes.…

Figure 3. Genetic determinants of hypertriglyceridemia. FCS and MCM both present with severe hypertriglyceridemia with TG levels ≥10 mmol/l (≥885 mmol/L), while TG levels in mild-to-moderate hypertriglyceridemia are lower, ranging from 2.0 to 9.9 mmol/L (175–885 mg/dL). FCS is a very rare condition and is the only true classical monogenic phenotype, showing recessive inheritance with biallelic variants in LPL, APOA5, APOC2, GPIHBP1, and LMF1 genes. MCM and mild-to-moderate hypertriglyceridemia have complex underlying genetics, showing statistical excess of heterozygous rare variants in LPL, APOA5, APOC2, GPIHBP1, and LMF1 genes or extreme polygenic scores or both, compared to the normal population, with frequencies denoted by color scheme as shown. Each phenotype shows 100 individuals and the proportion of relevant genetic factors, but note the extreme differences in population prevalence for each condition, which is not depicted here (please also refer to Figure 1). Non-genetic, environmental factors also play a role in expression of the complex phenotypes. FCS, familial chylomicronemia syndrome; MCM, multifactorial chylomicronemia; TG, triglyceride.