Skip to main content

Advertisement

SpringerLink
Log in

The Complex Genetic Basis of Plasma Triglycerides

  • Genetics (AJ Marian, Section Editor)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Demonstration of a direct relationship between plasma triglyceride (TG) concentration and atherosclerosis has proven difficult due to confounding variables that accompany elevated plasma TG, such as other dyslipidemias, obesity, and type 2 diabetes. However, human genetic studies have provided evidence suggesting a causal link between plasma TG and cardiovascular risk. Analyses in human patients with hypertriglyceridemia (HTG) also provides insight into the relationship between genetic variation, predisposition to elevated plasma TG, and risk of subsequent cardiovascular disease. Here, we review recent key studies that have contributed to our understanding of the genetic determinants of plasma TG concentration, including HTG susceptibility and phenotypic heterogeneity, and discuss our maturing model of the allelic and phenotypic spectrum of plasma TG.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Bansal S, Buring JE, Rifai N, et al. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA. 2007;298:309–16.

    Article  PubMed  CAS  Google Scholar 

  2. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299–308.

    Article  PubMed  CAS  Google Scholar 

  3. • Goldberg IJ, Eckel RH, McPherson R. Triglycerides and heart disease: still a hypothesis? Arterioscler Thromb Vasc Biol. 2011;31:1716–25. This is a thorough recent review addressing the evidence supporting both direct and indirect relationships between plasma TG concentration and cardiovascular disease.

    Article  PubMed  CAS  Google Scholar 

  4. Talayero BG, Sacks FM. The role of triglycerides in atherosclerosis. Curr Cardiol Rep. 2011;13:544–52.

    Article  PubMed  Google Scholar 

  5. Sarwar N, Sandhu MS, Ricketts SL, et al. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet. 2010;375:1634–9.

    Article  PubMed  CAS  Google Scholar 

  6. Nordestgaard BG, Tybjaerg-Hansen A. Genetic determinants of LDL, lipoprotein(a), triglyceride-rich lipoproteins and HDL: concordance and discordance with cardiovascular disease risk. Curr Opin Lipidol. 2011;22:113–22.

    Article  PubMed  CAS  Google Scholar 

  7. Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007;176:1113–20.

    Article  PubMed  Google Scholar 

  8. Kirchgessner TG, LeBoeuf RC, Langner CA, et al. Genetic and developmental regulation of the lipoprotein lipase gene: loci both distal and proximal to the lipoprotein lipase structural gene control enzyme expression. J Biol Chem. 1989;264:1473–82.

    PubMed  CAS  Google Scholar 

  9. LaRosa JC, Levy RI, Herbert P, et al. A specific apoprotein activator for lipoprotein lipase. Biochem Biophys Res Commun. 1970;41:57–62.

    Article  PubMed  CAS  Google Scholar 

  10. Charlton-Menys V, Durrington PN. Apolipoprotein A5 and hypertriglyceridemia. Clin Chem. 2005;51:295–7.

    Article  PubMed  CAS  Google Scholar 

  11. Peterfy M, Ben-Zeev O, Mao HZ, et al. Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia. Nat Genet. 2007;39:1483–7.

    Article  PubMed  CAS  Google Scholar 

  12. Davies BS, Beigneux AP, Fong LG, Young SG. New wrinkles in lipoprotein lipase biology. Curr Opin Lipidol. 2012;23:35–42.

    Google Scholar 

  13. • Johansen CT, Hegele RA. Allelic and phenotypic spectrum of plasma triglycerides. Biochim Biophys Acta 2011:In press. This is a comprehensive review first describing our model for the allelic and phenotypic spectrum of plasma TG and HTG susceptibility.

  14. Priore Oliva C, Pisciotta L, Li Volti G, et al. Inherited apolipoprotein A-V deficiency in severe hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2005;25:411–7.

    Article  PubMed  Google Scholar 

  15. Marcais C, Verges B, Charriere S, et al. Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment. J Clin Invest. 2005;115:2862–9.

    Article  PubMed  CAS  Google Scholar 

  16. Priore Oliva C, Carubbi F, Schaap FG, et al. Hypertriglyceridaemia and low plasma HDL in a patient with apolipoprotein A-V deficiency due to a novel mutation in the APOA5 gene. J Intern Med. 2008;263:450–8.

    Article  PubMed  CAS  Google Scholar 

  17. Cefalu AB, Noto D, Arpi ML, et al. Novel LMF1 nonsense mutation in a patient with severe hypertriglyceridemia. J Clin Endocrinol Metab. 2009;94:4584–90.

    Article  PubMed  CAS  Google Scholar 

  18. Franssen R, Young SG, Peelman F, et al. Chylomicronemia with low postheparin lipoprotein lipase levels in the setting of GPIHBP1 defects. Circ Cardiovasc Genet. 2010;3:169–78.

    Article  PubMed  CAS  Google Scholar 

  19. Olivecrona G, Ehrenborg E, Semb H, et al. Mutation of conserved cysteines in the Ly6 domain of GPIHBP1 in familial chylomicronemia. J Lipid Res. 2010;51:1535–45.

    Article  PubMed  CAS  Google Scholar 

  20. Coca-Prieto I, Kroupa O, Gonzalez-Santos P et al. Childhood-onset chylomicronaemia with reduced plasma lipoprotein lipase activity and mass: identification of a novel GPIHBP1 mutation. J Intern Med. 2011;270:224–8.

    Google Scholar 

  21. Beigneux AP, Franssen R, Bensadoun A, et al. Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase. Arterioscler Thromb Vasc Biol. 2009;29:956–62.

    Article  PubMed  CAS  Google Scholar 

  22. Wang J, Hegele RA. Homozygous missense mutation (G56R) in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1) in two siblings with fasting chylomicronemia (MIM 144650). Lipids Health Dis. 2007;6:23.

    Article  PubMed  Google Scholar 

  23. Johansen CT, Kathiresan S, Hegele RA. Genetic determinants of plasma triglycerides. J Lipid Res. 2011;52:189–206.

    Article  PubMed  CAS  Google Scholar 

  24. Johansen CT, Wang J, Lanktree MB, et al. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat Genet. 2010;42:684–7.

    Article  PubMed  CAS  Google Scholar 

  25. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707–13.

    Article  PubMed  CAS  Google Scholar 

  26. Johansen CT, Wang J, Lanktree MB, et al. An increased burden of common and rare lipid-associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2011;31:1916–26.

    Article  PubMed  CAS  Google Scholar 

  27. Johansen CT, Hegele RA. Genetic bases of hypertriglyceridemic phenotypes. Curr Opin Lipidol. 2011;22:247–53.

    Article  PubMed  CAS  Google Scholar 

  28. Johansen CT, Wang J, McIntyre AD et al. Excess of rare variants in non-GWAS candidate genes in patients with hypertriglyceridemia. Circ Cardiovasc Genet. 2012;5:66–72. This is a rare variant accumulation study implicating non-GWAS candidate genes in HTG susceptibility using novel analytical strategies.

  29. Lee MW, Chanda D, Yang J, et al. Regulation of hepatic gluconeogenesis by an ER-bound transcription factor, CREBH. Cell Metab. 2010;11:331–9.

    Article  PubMed  CAS  Google Scholar 

  30. Lee JH, Giannikopoulos P, Duncan SA, et al. The transcription factor cyclic AMP-responsive element-binding protein H regulates triglyceride metabolism. Nat Med. 2011;17:812–5.

    Article  PubMed  CAS  Google Scholar 

  31. Gargalovic PS, Erbilgin A, Kohannim O, et al. Quantitative trait locus mapping and identification of Zhx2 as a novel regulator of plasma lipid metabolism. Circ Cardiovasc Genet. 2010;3:60–7.

    Article  PubMed  CAS  Google Scholar 

  32. Burnett JR, Hooper AJ. Common and rare gene variants affecting plasma LDL cholesterol. Clin Biochem Rev. 2008;29:11–26.

    PubMed  Google Scholar 

  33. Musunuru K, Pirruccello JP, Do R, et al. Exome Sequencing, Mutations in ANGPTL3, and Familial Combined Hypolipidemia. N Engl J Med. 2010;363:2220–7.

    Article  PubMed  CAS  Google Scholar 

  34. Pisciotta L, Favari E, Magnolo AL et al. Characterization of three kindreds with familial combined hypolipidemia due to loss of function mutations of ANGPTL3. Circ Cardiovasc Genet. 2012;5:42–50.

    Google Scholar 

  35. Romeo S, Yin W, Kozlitina J, et al. Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J Clin Invest. 2009;119:70–9.

    PubMed  CAS  Google Scholar 

  36. Romeo S, Pennacchio LA, Fu Y, et al. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat Genet. 2007;39:513–6.

    Article  PubMed  CAS  Google Scholar 

  37. Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science. 2008;322:1702–5.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

CTJ is supported by the Canadian Institutes of Health Research (CIHR) and the Canadian Gene Cure Foundation Scriver Family MD/PhD Scholarship, the University of Western Ontario MD/PhD program, and is a CIHR fellow in Vascular Research. RAH is supported by the Jacob J. Wolfe Distinguished Medical Research Chair at the University of Western Ontario, the Edith Schulich Vinet Canada Research Chair in Human Genetics (Tier I), the Martha G. Blackburn Chair in Cardiovascular Research, and operating grants from the CIHR (MOP-13430, MOP-79523, CTP-79853), the Heart and Stroke Foundation of Ontario (NA-6059, T-6018, PRG-4854), the Pfizer Jean Davignon Distinguished Cardiovascular and Metabolic Research Award, and Genome Canada through the Ontario Genomics Institute.

Disclosures

No conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Departments of Medicine and Biochemistry, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, ON, N6A 5K8, Canada

    Christopher T. Johansen & Robert A. Hegele

Authors
  1. Christopher T. Johansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert A. Hegele
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert A. Hegele.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Johansen, C.T., Hegele, R.A. The Complex Genetic Basis of Plasma Triglycerides. Curr Atheroscler Rep 14, 227–234 (2012). https://doi.org/10.1007/s11883-012-0243-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11883-012-0243-2

Keywords

Search

Navigation