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United States Department of Agriculture

Agricultural Research Service

Title: Fenofibrate Effect on Triglyceride and Postprandial Response of Apolipoprotein A5 Variants: The GOLDN Study

Authors
item Lai, Chao Qiang
item Arnett, Donna - UNIVERSITY OF ALABAMA
item Straka, Robert - UNIVERSITY OF MINNESOTA
item Tsai, Michael - UNIVERSITY OF MINNESOTA05
item Peacock, James - UNIVERSITY OF MINNESOTA
item Adiconis, Xian - TUFTS UNIVERSITY
item Parnell, Laurence
item Hixson, James - UNIVERSITY OF TEXAS
item Province, Michael - WASHINGTON UNIVERSITY
item Ordovas, Jose

Submitted to: Arteriosclerosis Thrombosis and Vascular Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: March 28, 2007
Publication Date: June 1, 2007
Citation: Lai, C., Arnett, D.K., Straka, R.J., Tsai, M.Y., Peacock, J.M., Adiconis, X., Parnell, L.D., Hixson, J.E., Province, M.A., Ordovas, J.M. 2007. Fenofibrate Effect on Triglyceride and Postprandial Response of Apolipoprotein A5 Variants: The GOLDN Study. Arteriosclerosis Thrombo Vasc Biol. 27:1417-1425.

Interpretive Summary: Elevated plasma triglyceride (TG) levels (hypertriglyceridemia), one of the characteristic features of the Metabolic Syndrome (MS), have been recognized as an independent risk factor of coronary heart disease (CHD). Drug and/or dietary intervention is often prescribed as a means to reduce TG levels and concomitantly to lower the CHD risk. One such class of therapeutics are the fibrates, of which fenofibrate (Tricor®) is a member, yet this drug displays considerable inter-subject variation in response and the reason for this may be due to genetic differences between individuals. Because the apolipoprotein A5 (APOA5) gene is a key determinant of plasma TG concentrations, we sought to examine the association between genetic variants of this gene and changes in TG and HDL-C levels after administration of fenofibrate in 791 men and women participating in the GOLDN study. After 3 weeks of drug treatment, individuals carrying the 56G variant of APOA5 displayed significant decreases in TG (p=0.0056), and increases in HDL-C (p=0.0097) levels after fasting relative to their pre-treatment values when compared to non-carriers. In the postprandial (after meal) response before fenofibrate treatment, the 56G carriers had higher TG and lower HDL-C levels (toward less healthy values) than the non-carriers. After drug intervention, the differential postprandial response disappeared (p=0.1434 and 0.6341, respectively). These beneficial responses of 56G carriers to fenofibrate were further characterized by a shift in cholesterol profile: increases in large HDL-C and large LDL-C concentration, and LDL-C size, and a decrease in total VLDL levels. However, the 56G carriers did not change significantly in response to the drug relative to non-carriers in terms of other lipid measures: LDL-C or total cholesterol, chylomicron, and CRP levels. A second, independent variant of APOA5, -1131T>C, showed no differential response to fenofibrate intervention. In conclusion, this study demonstrates that the APOA5 56G carriers benefited more from fenofibrate treatment than non-carriers in both lowering plasma TG and increasing HDL-C levels.

Technical Abstract: Elevated plasma triglyceride (TG) levels (hypertriglyceridemia), one of the characteristic features of the Metabolic Syndrome (MS), have been recognized as an independent risk factor of coronary heart disease (CHD). Lowering TG concentration by dietary or drug intervention reduces CHD risk. Fenofibrate, an agonist of peroxisome proliferative activated receptor alpha (PPARA), effectively reduces plasma TG levels, however this drug displays considerable inter-subject variation in response. One key source of this variation may be genetic. Because the apolipoprotein A5 (APOA5) gene is a key determinant of plasma TG concentrations, we sought to examine the association between key SNPs in this gene and TG and HDL-C response to fenofibrate and a postprandial lipid challenge in 791 men and women participating in the GOLDN study. After 3 weeks of drug treatment, APOA5 56G carriers displayed significant decrease in TG (p=0.0056), and increase in HDL-C (p=0.0097) levels relative to their basal values at the fasting state when compared to non-carriers. In the postprandial response at baseline (off drug), the 56G carriers had higher TG and lower HDL-C levels than the non-carriers. After drug intervention, the differential postprandial response disappeared (p=0.1434 and 0.6341, respectively). These diverse beneficial responses of 56G carriers to drug were further characterized as increases in large HDL-C and large LDL-C concentration, and LDL-C size, and as a decrease in total VLDL levels. However, the 56G carriers did not change significantly in response to the drug relative to non-carriers in LDL-C or total cholesterol, chylomicron, and CRP levels. On the other hand, subjects with different APOA5-1131T>C genotypes showed no differential response to fenofibrate intervention. In conclusion, this study demonstrated that the APOA5 56G carriers benefited more from fenofibrate treatment than non-carriers in lowering plasma TG and increasing HDL-C levels.

Last Modified: 11/24/2014