Recent Insights into the Genetics of Plasma Triglycerides and Possible Causal Mechanisms in Cardiovascular Disease


Plasma triglyceride (TG) concentration is an integrated measurement of circulating TG‐rich lipoproteins. The specific lipoprotein fractions and subfractions that contribute to this measurement differ between the fasting and nonfasting states. Although the association between fasting plasma TG concentration and cardiovascular disease (CVD) has been controversial, recent studies of nonfasting plasma TG and related biomarkers have rekindled interest in a possible direct causative relationship. Here, we review current understanding of the phenotypic and genetic spectrum of plasma TG concentrations, focusing on recent evidence from Mendelian randomisation studies that seem to implicate nonfasting TG and remnant cholesterol in CVD susceptibility. The totality of evidence suggests that nonfasting TG concentration, perhaps because of its relationship with remnant cholesterol, is causally associated with CVD outcomes.

Key Concepts:

  • Susceptibility to clinical hypertriglyceridaemia is determined by a burden of both common and rare variants, on which are superimposed secondary nongenetic factors.

  • The allelic and phenotypic spectrum of plasma triglyceride (TG) concentrations explains a variety of TG‐related phenotypes and their phenotypic heterogeneity.

  • Monogenic hypertriglyceridemias are associated with increased pancreatitis risk and result from rare mutations on both alleles of 6 different genes.

  • Nonfasting plasma TG concentration is closely associated with elevated remnant cholesterol concentrations; this may explain the relationship with cardiovascular risk.

  • Mendelian randomisation studies appear to implicate a causal relationship between both nonfasting plasma TG, and more recently remnant cholesterol levels as determinants of CVD risk.

  • The spectrum of genes newly implicated as being involved in plasma triglyceride metabolism has expanded the range of pathways and potential drug targets.

Keywords: genetic variation; plasma triglyceride; hypertriglyceridaemia; hyperlipoproteinaemia; nonfasting plasma triglyceride; remnant cholesterol; mendelian randomisation; cardiovascular disease

Figure 1.

Contribution of genetic variants in TG‐associated genes to the allelic and phenotypic spectrum of plasma TG concentrations. Cells are shaded to indicate the relative contribution of common and rare variants to each respective TG phenotype. Monogenic phenotypes are caused by rare homozygous variants of individually large effect, whereas the contribution of common variants is much less relevant in these conditions, which are often paediatric. Polygenic phenotypes are caused by a combination of rare and common variants, either in genes that inhibit or modulate TG‐metabolism causing very low plasma TG, or in genes that are essential to metabolise TG‐rich lipoproteins causing very high plasma TG. Normal TG concentrations are caused by a balance of both common and rare variants of individually small effect, in genes that either increase or decrease plasma TG concentrations. This model is simplified: TG phenotypes are arbitrarily defined, but truly represent a spectrum of phenotypes dependent on underlying variation. However, each phenotype depends on the relative contribution of common and rare variants found in any number of genes. Cells containing question marks indicate assumed gene involvement in a phenotype, where results have never been proven.

Figure 2.

The allelic spectrum of plasma TG concentrations explains hypertriglyceridaemia (hyperTG) susceptibility and phenotypic heterogeneity among the classically defined hyperlipoproteinaemia (HLP) phenotypes. A balance of normal and protective TG‐associated risk alleles results in normal TG concentrations, whereas an accumulation of TG‐associate risk alleles provides a foundation of hyperTG susceptibility. A critical accumulation of common variants (CV), rare variants (RV) and secondary environmental exposures (such as diet, obesity, metabolic syndrome (MetS) or type 2 diabetes (T2D)) is sufficient to cause expression of HLP type 4 (hypertriglyceridaemia). The accumulation of TG‐associated common variants that are jointly associated with low‐density lipoprotein cholesterol (LDL‐C) transform HLP type 4 into HLP type 2b (combined hyperlipidaemia). The presence of two receptor‐binding defective APOE E2 alleles on a background of susceptibility to hyperTG hastens manifestation of the HLP type 3 (dysbetalipoproteinaemia) phenotype. Finally, the added effects of particularly damaging mutations, heterozygous APOE E2 alleles and extreme secondary factors push the phenotypes towards the more extreme HLP type 5 (mixed hyperlipidaemia).

Figure 3.

Schematic of the Mendelian randomisation (MR) framework and possible sources of confounding relating to TG‐rich lipoprotein metabolism. MR presumes that if a genetic variant or genetic risk score (GRS) is proportionally associated with both an intermediate trait and disease endpoint, then a causal relationship likely exists between the trait and disease endpoint. However, biological confounders including linkage disequilibrium and pleiotropy may interfere with such presumptions of causality if the genetic instrument is associated with other metabolic pathways or other genes with their own involvement in disease pathophysiology.



ter Avest E, Holewijn S, Bredie SJ et al. (2007) Remnant particles are the major determinant of an increased intima media thickness in patients with familial combined hyperlipidemia (FCH). Atherosclerosis 191(1): 220–226.

Bansal S, Buring JE, Rifai N et al. (2007) Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. Journal of the American Medical Association 298(3): 309–316.

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.

Boden WE, Probstfield JL, Anderson T et al. (2011) Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. New England Journal of Medicine 365(24): 2255–2267.

Clarke R, Peden JF, Hopewell JC et al. (2009) Genetic variants associated with lp(a) lipoprotein level and coronary disease. New England Journal of Medicine 361(26): 2518–2528.

Dallongeville J and Meirhaeghe A (2010) Triglyceride‐mediated pathways and coronary heart disease. Lancet 376(9745): 956–957.

Davey Smith G and Ebrahim S (2003) ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? International Journal of Epidemiology 32(1): 1–22.

Elliott P, Chambers JC, Zhang W et al. (2009) Genetic loci associated with c‐reactive protein levels and risk of coronary heart disease. Journal of the American Medical Association 302(1): 37–48.

Fredrickson DS and Lees RS (1965) A system for phenotyping hyperlipoproteinemia. Circulation 31321–31327.

Freiberg JJ, Tybjaerg‐Hansen A, Jensen JS et al. (2008) Nonfasting triglycerides and risk of ischemic stroke in the general population. Journal of the American Medical Association 300(18): 2142–2152.

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

Hopkins PN, Wu LL, Hunt SC et al. (2005) Plasma triglycerides and type III hyperlipidemia are independently associated with premature familial coronary artery disease. Journal of the American College of Cardiology 45(7): 1003–1012.

Johansen CT and Hegele RA (2011) Genetic bases of hypertriglyceridemic phenotypes. Current Opinion in Lipidology 22(4): 247–253.

Johansen CT and Hegele RA (2012a) Allelic and phenotypic spectrum of plasma triglycerides. Biochimica et Biophysica Acta 1821(5): 833–842.

Johansen CT and Hegele RA (2012b) The complex genetic basis of plasma triglycerides. Current Atherosclerosis Reports 14(3): 227–234.

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. (2010) Excess of rare variants in genes identified by genome‐wide association study of hypertriglyceridemia. Nature Genetics 42(8): 684–687.

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.

Jorgensen AB, Frikke‐Schmidt R, West AS et al. (2012) Genetically elevated non‐fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. European Heart Journal 34(24): 1826–1833.

Kamstrup PR, Tybjaerg‐Hansen A, Steffensen R et al. (2009) Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. Journal of the American Medical Association 301(22): 2331–2339.

Karpe F, Boquist S, Tang R et al. (2001) Remnant lipoproteins are related to intima‐media thickness of the carotid artery independently of LDL cholesterol and plasma triglycerides. Journal of Lipid Research 42(1): 17–21.

Langsted A, Freiberg JJ, Tybjaerg‐Hansen A et al. (2011) Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen city heart study with 31 years of follow‐up. Journal of Internal Medicine 270(1): 65–75.

Lawlor DA, Harbord RM, Sterne JA et al. (2008) Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Statistics in Medicine 27(8): 1133–1163.

Mahley RW, Huang Y and Rall SC Jr (1999) Pathogenesis of type iii hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. Journal of Lipid Research 40(11): 1933–1949.

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.

Martin‐Campos JM, Roig R, Mayoral C et al. (2012) Identification of a novel mutation in the angptl3 gene in two families diagnosed of familial hypobetalipoproteinemia without apob mutation. Clinica Chimica Acta 413(5–6): 552–555.

Minicocci I, Montali A, Robciuc MR et al. (2012) Mutations in the angptl3 gene and familial combined hypolipidemia: a clinical and biochemical characterization. Journal of Clinical Endocrinology and Metabolism 97(7): E1266–E1275.

Musunuru K, Pirruccello JP, Do R et al. (2010) Exome sequencing, angptl3 mutations, and familial combined hypolipidemia. New England Journal of Medicine 363(23): 2220–2227.

Nordestgaard BG, Benn M, Schnohr P et al. (2007) Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. Journal of the American Medical Association 298(3): 299–308.

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 Zilversmit DB (1988) Large lipoproteins are excluded from the arterial wall in diabetic cholesterol‐fed rabbits. Journal of Lipid Research 29(11): 1491–1500.

Pisciotta L, Favari E, Magnolo L et al. (2012) Characterization of three kindreds with familial combined hypolipidemia caused by loss‐of‐function mutations of angptl3. Circulation: Cardiovascular Genetics 5(1): 42–50.

Pollin TI, Damcott CM, Shen H et al. (2008) A null mutation in human apoc3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 322(5908): 1702–1705.

Rader DJ and Tall AR (2012) The not‐so‐simple HDL story: is it time to revise the HDL cholesterol hypothesis? Nature Medicine 18(9): 1344–1346.

Robciuc MR, Maranghi M, Lahikainen A et al. (2013) Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arteriosclerosis, Thrombosis, and Vascular Biology 33(7): 1706–1713.

Romeo S, Yin W, Kozlitina J et al. (2009) Rare loss‐of‐function mutations in angptl family members contribute to plasma triglyceride levels in humans. Journal of Clinical Investigation 119(1): 70–79.

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.

Schwartz GG, Olsson AG, Abt M et al. (2012) Effects of dalcetrapib in patients with a recent acute coronary syndrome. New England Journal of Medicine 367(22): 2089–2099.

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 11(3): 569–577.

Sheehan NA, Didelez V, Burton PR et al. (2008) Mendelian randomisation and causal inference in observational epidemiology. PLoS Medicine 5(8): e177.

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.

Talmud PJ, Hawe E, Martin S et al. (2002) Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides. Human Molecular Genetics 11(24): 3039–3046.

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. (2012) Remnant cholesterol as a causal risk factor for ischemic heart disease. Journal of the American College of Cardiology 61(4): 427–436.

Varbo A, Nordestgaard BG, Tybjaerg‐Hansen A et al. (2011) Nonfasting triglycerides, cholesterol, and ischemic stroke in the general population. Annals of Neurology 69(4): 628–634.

Voight BF, Peloso GM, Orho‐Melander M et al. (2012) Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 380(9841): 572–580.

Zacho J, Tybjaerg‐Hansen A, Jensen JS et al. (2008) Genetically elevated c‐reactive protein and ischemic vascular disease. New England Journal of Medicine 359(18): 1897–1908.

Zilversmit DB (1979) Atherogenesis: a postprandial phenomenon. Circulation 60(3): 473–485.

Further Reading

McPherson R (2013) Remnant cholesterol: “Non‐(HDL‐C+LDL‐C)” As a coronary artery disease risk factor. Journal of the American College of Cardiology 61(4): 437–439.

Nakajima K, Nakano T, Tokita Y et al. (2012) The characteristics of remnant lipoproteins in the fasting and postprandial plasma. Clinica Chimica Acta 413(13–14): 1077–1086.

Varbo A, Benn M, Tybjaerg‐Hansen A et al. (2013) Elevated remnant cholesterol causes both low‐grade inflammation and ischemic heart disease, while elevated low‐density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation 128(12): 1298–1309.

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Johansen, Christopher T, MacDonald, Austin, and Hegele, Robert A(Dec 2013) Recent Insights into the Genetics of Plasma Triglycerides and Possible Causal Mechanisms in Cardiovascular Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025307]