Molecular Genetics of Hypertriglyceridaemia

Abstract

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

References

Basel‐Vanagaite L, Zevit N, Har Zahav A, et al. (2012) Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol‐3‐phosphate dehydrogenase 1. American Journal of Human Genetics 90 (1): 49–60.

Benlian P, De Gennes JL, Foubert L, et al. (1996) Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene. New England Journal of Medicine 335 (12): 848–854.

Berglund L, Brunzell JD, Goldberg AC, et al. (2012) Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 97 (9): 2969–2989.

Boullart AC, de Graaf J and Stalenhoef AF (2012) Serum triglycerides and risk of cardiovascular disease. Biochimica et Biophysica Acta 1821 (5): 867–875.

Brahm A and Hegele RA (2013) Hypertriglyceridemia. Nutrients 5 (3): 981–1001.

Brahm AJ and Hegele RA (2015) Chylomicronaemia—current diagnosis and future therapies. Nature Reviews Endocrinology 11 (6): 352–362.

Chang Y‐C, Yu Y‐H and Chuang L‐M (2013) Molecular Genetics of Metabolic Syndrome (In: eLS). John Wiley & Sons, Ltd, Chichester, UK. http://www.els.net 10.1002/9780470015902.a0024320

Chapman MJ, Ginsberg HN, Amarenco P, et al. (2011) Triglyceride‐rich lipoproteins and high‐density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. European Heart Journal 32 (11): 1345–1361.

Chokshi N, Blumenschein SD, Ahmad Z, et al. (2014) Genotype–phenotype relationships in patients with type I hyperlipoproteinemia. Journal of Clinical Lipidology 8 (3): 287–295.

Doolittle MH, Ehrhardt N and Peterfy M (2010) Lipase maturation factor 1: structure and role in lipase folding and assembly. Current Opinion in Lipidology 21 (3): 198–203.

Feoli‐Fonseca JC, Levy E, Godard M, et al. (1998) Familial lipoprotein lipase deficiency in infancy: clinical, biochemical, and molecular study. Journal of Pediatrics 133 (3): 417–423.

Forte TM, Sharma V and Ryan RO (2016) Apolipoprotein A‐V gene therapy for disease prevention/treatment: a critical analysis. Journal of Biomedical Research 30 (2): 88–93.

Goldberg IJ, Eckel RH and McPherson R (2011) Triglycerides and heart disease: still a hypothesis? Arteriosclerosis, Thrombosis, and Vascular Biology 31 (8): 1716–1725.

Gotoda T, Shirai K, Ohta T, et al. (2012) Diagnosis and management of type I and type V hyperlipoproteinemia. Journal of Atherosclerosis and Thrombosis 19 (1): 1–12.

Hegele RA, Ban MR, Hsueh N, et al. (2009) A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia. Human Molecular Genetics 18 (21): 4189–4194.

Hegele RA and Pollex RL (2009) Hypertriglyceridemia: phenomics and genomics. Molecular and Cellular Biochemistry 326 (1–2): 35–43.

Hegele RA, Ginsberg HN, Chapman MJ, et al. (2014) The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet. Diabetes & Endocrinology 2 (8): 655–666.

Hegele RA, Ban MR, Cao H, et al. (2015) Targeted next‐generation sequencing in monogenic dyslipidemias. Current Opinion in Lipidology 26 (2): 103–113.

Hegele RA (2016) Multidimensional regulation of lipoprotein lipase: impact on biochemical and cardiovascular phenotypes. Journal of Lipid Research 57 (9): 1601–1607.

Hokanson JE and Austin MA (1996) Plasma triglyceride level is a risk factor for cardiovascular disease independent of high‐density lipoprotein cholesterol level: a meta‐analysis of population‐based prospective studies. Journal of Cardiovascular Risk 3 (2): 213–219.

Johansen CT, Wang J, Lanktree MB, et al. (2010) Excess of rare variants in genes identified by genome‐wide association study of hypertriglyceridemia. Nature Genetics 42 (8): 684–687.

Johansen CT, Kathiresan S and Hegele RA (2011a) Genetic determinants of plasma triglycerides. Journal of Lipid Research 52 (2): 189–206.

Johansen CT, Wang J, Lanktree MB, et al. (2011b) An increased burden of common and rare lipid‐associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia. Arteriosclerosis, Thrombosis, and Vascular Biology 31 (8): 1916–1926.

Johansen CT, Wang J, McIntyre AD, et al. (2012) Excess of rare variants in non‐genome‐wide association study candidate genes in patients with hypertriglyceridemia. Circulation. Cardiovascular Genetics 5 (1): 66–72.

Jong MC, Hofker MH and Havekes LM (1999) Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3. Arteriosclerosis, Thrombosis, and Vascular Biology 19 (3): 472–484.

Jorgensen AB, Frikke‐Schmidt R, West AS, et al. (2013) Genetically elevated non‐fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. European Heart Journal 34 (24): 1826–1833.

Kardia, SLR (2007) Gene–Environment Interaction (In: eLS). John Wiley & Sons, Ltd, Chichester, UK. http://www.els.net 10.1002/9780470015902.a0005413.pub2

Kathiresan S, Willer CJ, Peloso GM, et al. (2009) Common variants at 30 loci contribute to polygenic dyslipidemia. Nature Genetics 41 (1): 56–65.

Kei AA, Filippatos TD, Tsimihodimos V, et al. (2012) A review of the role of apolipoprotein C‐II in lipoprotein metabolism and cardiovascular disease. Metabolism 61 (7): 906–921.

Kennedy MA (2005) Mendelian Genetic Disorders (In: eLS). John Wiley & Sons, Ltd, Chichester, UK. http://www.els.net 10.1038/npg.els.0003934

Lambert JE and Parks EJ (2012) Postprandial metabolism of meal triglyceride in humans. Biochimica et Biophysica Acta 1821 (5): 721–726.

Lee JH, Giannikopoulos P, Duncan SA, et al. (2011) The transcription factor cyclic AMP‐responsive element‐binding protein H regulates triglyceride metabolism. Nature Medicine 17 (7): 812–815.

Lewis GF, Xiao C and Hegele RA (2015) Hypertriglyceridemia in the genomic era: a new paradigm. Endocrinology Reviews 36 (1): 131–147.

Mamo JC, Proctor SD and Smith D (1998) Retention of chylomicron remnants by arterial tissue; importance of an efficient clearance mechanism from plasma. Atherosclerosis 141 (Suppl 1): S63–S69.

Nordestgaard BG, Wootton R and Lewis B (1995) Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima‐inner media. Arteriosclerosis, Thrombosis, and Vascular Biology 15 (4): 534–542.

Nordestgaard BG and Varbo A (2014) Triglycerides and cardiovascular disease. Lancet 384 (9943): 626–635.

Rahalkar AR and Hegele RA (2008) Monogenic pediatric dyslipidemias: classification, genetics and clinical spectrum. Molecular Genetics and Metabolism 93 (3): 282–294.

Rees MG, Raimondo A, Wang J, et al. (2014) Inheritance of rare functional GCKR variants and their contribution to triglyceride levels in families. Human Molecular Genetics 23 (20): 5570–5578.

Sarwar N, Sandhu MS, Ricketts SL, et al. (2010) Triglyceride‐mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet 375 (9726): 1634–1639.

Shaikh M, Wootton R, Nordestgaard BG, et al. (1991) Quantitative studies of transfer in vivo of low density, Sf 12–60, and Sf 60–400 lipoproteins between plasma and arterial intima in humans. Arteriosclerosis and Thrombosis: A Journal of Vascular Biology 11 (3): 569–577.

Surendran RP, Visser ME, Heemelaar S, et al. (2012) Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. Journal of Internal Medicine 272 (2): 185–196.

Teslovich TM, Musunuru K, Smith AV, et al. (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466 (7307): 707–713.

Varbo A, Benn M, Tybjaerg‐Hansen A, et al. (2013) Remnant cholesterol as a causal risk factor for ischemic heart disease. Journal of the American College of Cardiology 61 (4): 427–436.

Wang J, Cao H, Ban MR, et al. (2007) Resequencing genomic DNA of patients with severe hypertriglyceridemia (MIM 144650). Arteriosclerosis, Thrombosis, and Vascular Biology 27 (11): 2450–2455.

Wang J, Ban MR, Kennedy BA, et al. (2008a) APOA5 genetic variants are markers for classic hyperlipoproteinemia phenotypes and hypertriglyceridemia. Nature Clinical Practice. Cardiovascular Medicine 5 (11): 730–737.

Wang J, Ban MR, Zou GY, et al. (2008b) Polygenic determinants of severe hypertriglyceridemia. Human Molecular Genetics 17 (18): 2894–2899.

Willer CJ, Schmidt EM, Sengupta S, et al. (2013) Discovery and refinement of loci associated with lipid levels. Nature Genetics 45 (11): 1274–1283.

Young SG and Zechner R (2013) Biochemistry and pathophysiology of intravascular and intracellular lipolysis. Genes & Development 27 (5): 459–484.

Zambon A, Torres A, Bijvoet S, et al. (1993) Prevention of raised low‐density lipoprotein cholesterol in a patient with familial hypercholesterolaemia and lipoprotein lipase deficiency. Lancet 341 (8853): 1119–1121.

Zilversmit DB (1995) Atherogenic nature of triglycerides, postprandial lipidemia, and triglyceride‐rich remnant lipoproteins. Clinical Chemistry 41 (1): 153–158.

Further Reading

Blackett PR, Wilson DP and McNeal CJ (2015) Secondary hypertriglyceridemia in children and adolescents. Journal of Clinical Lipidology 9 (5 Suppl): S29–S40.

Brahm AJ and Hegele RA (2016) Combined hyperlipidemia: familial but not (usually) monogenic. Current Opinions in Lipidology 27 (2): 131–140.

Do R, Willer CJ, Schmidt EM, et al. (2015) Common variants associated with plasma triglycerides and risk for coronary artery disease. Nature Genetics 45 (2): 1345–1352.

Gryn SE and Hegele RA (2015) Novel therapeutics in hypertriglyceridemia. Current Opinions in Lipidology 26 (6): 484–491.

Schaefer EW, Leung A, Kravarusic J, et al. (2012) Management of severe hypertriglyceridemia in the hospital: a review. Journal of Hospital Medicine 7 (5): 431–438.

Stone NJ (1994) Secondary causes of hyperlipidemia. Medical Clinics of North America 78 (1): 117–141.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

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