Variants of Lipid-Related Genes in Adult Japanese Patients with Severe Hypertriglyceridemia

J Atheroscler Thromb. 2020 Dec 1;27(12):1264-1277. doi: 10.5551/jat.51540. Epub 2020 Feb 29.


Aim: Hypertriglyceridemia is a type of dyslipidemia that contributes to atherosclerosis and coronary heart disease. Variants in lipoprotein lipase (LPL), apolipoprotein CII (APOC2), apolipoprotein AV (APOA5), glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), lipase maturation factor 1 (LMF1), and glucokinase regulator (GCKR) are responsible for hypertriglyceridemia. We investigated the molecular basis of severe hypertriglyceridemia in adult patients referred to the Clinical Laboratory at Fukuoka University Hospital.

Methods: Twenty-three adult patients with severe hypertriglyceridemia (>1,000 mg/dL, 11.29 mmol/L) were selected. The coding regions of candidate genes were sequenced by next-generation sequencing. Forty-nine genes reportedly associated with hypertriglyceridemia were analyzed.

Results: In the 23 patients, we detected 70 variants: 28 rare and 42 common ones. Among the 28 rare variants with <1% allele frequency, p.I4533L in APOB, p.M490I in MLXIPL, p.L152M in NCAN, and p.S264T in TIMD4 were novel. We did not observe single gene homozygous or compound heterozygous disease-causing rare variants in any of the 23 hypertriglyceridemia cases. However, in silico algorithms and previous reports indicated that five rare variants, APOA5 (p.T184S), GCKR (c.354+1G>A), LMF1 (p.G410R), and LRP1 (p.G813R; p.R2173Q), and seven common variants, APOA5 (pG185C), APOE (p.C130R; p.E262K/p.E263K), GCKR (p.V103M), GPIHBP1 (p.C14F), LRP1 (p.Y4054F), and MLXIPL (p.Q241H), can cause hypertriglyceridemia. However, all five disease-causing rare variants detected in this study were heterozygous.

Conclusions: The prevalence of disease-causing rare variants in candidate genes in severe hypertriglyceridemia patients was low. The major causes of severe hypertriglyceridemia were not single gene abnormalities, but involved multiple gene variations and environmental factors.

Keywords: Chylomicronemia; Mutation; Next-generation sequencing; Severe hypertriglyceridemia; Variant.

MeSH terms

  • Adult
  • Apolipoproteins B / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Hypertriglyceridemia / epidemiology
  • Hypertriglyceridemia / genetics*
  • Japan / epidemiology
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Neurocan / genetics
  • Point Mutation
  • Young Adult


  • Apolipoproteins B
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • MLXIP protein, human
  • Membrane Proteins
  • Neurocan
  • TIMD4 protein, human
  • NCAN protein, human