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R3i EDITORIAL

10 August 2009

Fasting versus nonfasting triglycerides: Importance of triglyceride-regulating genetic polymorphisms to residual cardiovascular risk

Robert S. Rosenson

Division of Cardiovascular Medicine, University of Michigan, Ann Arbor,USA
Robert S. Rosenson In the past few years, there has been a substantial increase in our appreciation of the importance of postprandial triglycerides (TG) as a predictor of major cardiovascular events. Elevated non-fasting triglyceride concentrations have been associated with an increased risk of cardiovascular events and death in men 1 and women.1-4

Postprandial lipid responses vary considerably among individuals,5 and this variable response is influenced by fasting triglyceride concentration, insulin resistance and genetic regulation. Many studies have reported that genetic variants of genes involved in lipid and lipoprotein metabolism are associated with heterogeneity in postprandial responses and the risk of cardiovascular disease.

The Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study provides important genetic insights into variable postprandial responses.6 The contribution of minor alleles that regulate TG metabolism (APOA5 and -1131T>C genotypes) was investigated in normolipidemic subjects after a standardized oral fat load. APOA5, a primarily hepatic synthesized protein, is extensively involved in TG-metabolism where it has been demonstrated to act as a peroxisome proliferator-activated receptor alpha response element. In primary human cell cultures and experimental animal studies , APOA5 has been shown to inhibit VLDL production7 and facilitate VLDL clearance through activation of lipoprotein lipase (LPL).8 In GOLDN, the TG-lowering and HDL-C raising effects of fenofibrate therapy were larger in APOA5 56G carriers than non-carriers. The minor allele -1131C carriers (TC + CC) had significantly higher fasting and postprandial triglyceride concentrations than non-carriers (TT), but similar HDL-C levels. Unlike subjects with the APOA5 56C>G genotypes who responded differently to fenofibrate treatment, subjects with APOA5 and 1131T>C genotype reacted similarly to fenofibrate as non-carriers.

Evaluation of minor genes regulating postprandial lipemia provides a basis for the variable postprandial responses to fenofibrate therapy. The translation of this information on risk markers requires corroboration in clinical cardiovascular outcomes trials.


References

1. 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.

2. Stensvold I, Tverdal A, Urdal P, Graff-Iversen S. Non-fasting serum triglyceride concentration and mortality from coronary heart disease and any cause in middle aged norwegian women. BMJ. 1993;307:1318-1322.

3. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA. 2007;298:309-316.

4. Freiberg JJ, Tybjaerg-Hansen A, Jensen JS, Nordestgaard BG. Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA. 2008;300:2142-2152.

5. Rosenson RS, Wolff DA, Huskin AL, Helenowski IB, Rademaker AW. Fenofibrate therapy ameliorates fasting and postprandial lipoproteinemia, oxidative stress, and the inflammatory response in subjects with hypertriglyceridemia and the metabolic syndrome. Diabetes Care. 2007;30:1945-1951.br>
6. Rosenson RS. A treasure of pharmacogenomic insights into postprandial lipoproteinemia and therapeutic responses to fibrate therapy: Lessons from GOLDN. Curr Atheroscler Rep. 2009 May;11(3):161-164.

7. Schaap FG, Rensen PCN, Voshol PJ, Vrins C, van der Vliet HN, Chamuleau RAFM, Havekes LM, Groen AK, van Dijk KW. ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. J. Biol. Chem. 2004;279:27941-27947.

8. Fruchart-Najib J, Baugé E, Niculescu L-S, Pham T, Thomas B, Rommens C, Majd Z, Brewer B, Pennacchio LA, Fruchart J-C. Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5. Biochem Biophys Res Commun. 2004;319:397-404.