The effect of IL 6-174 C / G polymorphism on postprandial triglyceride metabolism in the GOLDN study

Chronically elevated interleukin-6 (IL-6) affects lipid and lipoprotein metabolism. Individuals genetically predisposed to higher IL-6 secretion may be at risk of dyslipidemia, especially during the postprandial phase. We investigated the effect of genetic variants at the IL6 locus on postprandial lipemia in US Whites participating in the Genetics of Lipid Lowering Drugs and Diet Network study. Subjects were given a single fat load composed of 3% of calories as protein, 14% as carbohydrate, and 83% as fat. Blood was drawn at 0 h, 3.5 h, and 6 h to determine plasma triglyceride (TG), TG-rich lipoprotein (TRL) and lipoprotein particle size. Homozygotes (GG) and heterozygotes (CG) of the -174C/G variant displayed higher plasma IL-6 concentrations compared with major allele homozygotes (CC) (P 5 0.029). GG and CG subjects showed higher fasting plasma TG (P 5 0.025), VLDL (P 5 0.04), and large VLDL (P 5 0.02) concentrations than did CC subjects. Moreover, GG and CG subjects experienced greater postprandial response of TG (P 5 0.006) and TRL, including chylomicrons (P 5 0.005), total VLDL (P 5 0.029), and large VLDL (P 5 0.017) than did CC subjects. These results suggest that the functional polymorphism -174C.G at the IL6 locus determines the difference in both fasting and postprandial TG metabolism. This phenomenon could be responsible for the observed association of this genetic variant with cardiovascular disease risk. —Shen, J., D. K. Arnett, P. Pérez-Martínez, L. D. Parnell, C-Q. Lai, J. M. Peacock, J. E. Hixson, M. Y. Tsai, R. J. Straka, P. N. Hopkins, and J. M. Ordovás. The effect of IL6-174C/G polymorphism on postprandial triglyceride metabolism in the GOLDN study. J. Lipid Res. 2008. 49: 1839–1845. Supplementary key words inflammation • fat load • postprandial response • triglyceride-rich lipoproteins • cardiovascular disease Current evidence indicates that inflammation plays an instrumental role in atherosclerosis development (1). A number of markers of inflammation, namely fibrinogen, highly sensitive C-reactive protein, interleukin-6 (IL-6), myeloperoxidase, and soluble CD40 ligand, have been explored as means of predicting cardiovascular disease (CVD) (2). Moreover, chronic inflammation has been shown to associate with alterations of lipid and lipoprotein metabolism (3). A more atherogenic lipid profile, characterized by increased triglyceride (TG), small, dense LDLs, and decreased HDL cholesterol (HDL-C), is common among patients with chronic inflammatory diseases such as HIV and rheumatoid arthritis and metabolic abnormalities with a strong inflammatory basis, including obesity, diabetes, and metabolic syndrome (4–8). Moreover, those patients typically experience an elevated postprandial lipemia (PPL) (4, 9–11), which leads to the production of atherogenic triglyceride-rich lipoprotein (TRL) and activation of thrombotic processes (12, 13). It has been well documented that PPL response varies considerably between individuals and is subject to genetic regulation. Thus, many studies have reported that genetic variants of genes involved in the lipid and lipoprotein metabolic pathway are associated with the extent and magniThis study was supported by contract 53-K06-5-10 from NIH and 58-1950-9001 from the US Department of Agriculture (Agriculture Research Service) and by NIH Heart, Lung and Blood Institute grants U 01 HL72524, Genetic and Environmental Determinants of Triglycerides and HL54776. Manuscript received 24 September 2007 and in revised form 19 February 2008 and in re-revised form 15 April 2008. Published, JLR Papers in Press, April 16, 2008. DOI 10.1194/jlr.P700033-JLR200 Abbreviations: CVD, cardiovascular disease; GOLDN, Genetics of Lipid Lowering Drugs and Diet Network; IL-6, interleukin-6; PPL, postprandial lipemia; SNP, single-nucleotide polymorphism; TG, triglyceride; TRL, TG-rich lipoprotein. To whom correspondence should be addressed. e-mail: jose.ordovas@tufts.edu The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of four tables. This article is available online at http://www.jlr. org Journal of Lipid Research Volume 49, 2008 1839 at P E N N S T A T E U N IV E R S IT Y , on F ebuary 3, 2013 w w w . j.org D ow nladed fom 0.DC1. html http://www.jlr. org/content/suppl/2008/04/18/P700033-JLR20 Supplemental Material can be found at: