Molecular Genetics of Hypertriglyceridaemia


Hypertriglyceridemia (HTG) is a commonly encountered medical condition defined by elevated fasting plasma triglyceride (TG) levels. The degree of elevation may range from mild to severe, with clinical features ranging from asymptomatic to increased vascular disease susceptibility to life‐threatening pancreatitis. While numerous nongenetic secondary factors play a strong contributory role, a genetic component is frequently present in patients who clinically express HTG. Purely monogenic or Mendelian HTG – for example autosomal recessive chylomicronemia – is exceedingly rare and results from bi‐allelic mutations affecting lipolysis. The pool of patients with more common polygenic HTG has an increased frequency of heterozygous large‐effect rare variants in LPL (lipoprotein lipase) and related genes, together with a high burden of small‐effect common polymorphisms, although any particular variant is not definitively causative in this condition.

Key Concepts

  • Hypertriglyceridemia (HTG) ranges from mild to severe, with the role of genetic determinants increasing with a more severe clinical presentation.
  • One definition proposes that plasma triglyceride (TG) levels in mild‐to‐moderate HTG are between 2.0 and 9.9 mmol L−1 (175 and 885 mg dL−1), while in severe HTG, levels exceed 10 mmol L−1 (885 mg dL−1).
  • A gamut of secondary factors can contribute to clinical expression of HTG.
  • Clinical consequences of HTG range from increased vascular disease risk to visible lipid eruptions on the skin to life‐threatening pancreatitis, depending on the affected species of lipoprotein particles and associated disturbances.
  • Monogenic chylomicronemia is an extreme and rare form of severe HTG that results from bi‐allelic mutations in LPL, APOC2, APOA5, LMF1, or GPIHBP1 genes.
  • Most other HTG cases have a polygenic basis: this patient pool harbours an assortment of genetic variants, including a high burden of rare heterozygous large‐effect variants and common small‐effect variants.

Keywords: monogenic; polygenic; complex trait; chylomicrons; very‐low density lipoprotein (VLDL); remnants; chylomicronemia; pancreatitis; vascular disease; secondary metabolic factors


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Further Reading

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Dron, Jacqueline S, and Hegele, Robert A(Mar 2017) Molecular Genetics of Hypertriglyceridaemia. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026710]