Abstract
Fenofibrate lowers triglycerides (TG) and raises high density lipoprotein cholesterol (HDLc) in dyslipidemic individuals. Several studies have shown genetic variability in lipid responses to fenofibrate treatment. It is, however, not known whether epigenetic patterns are also correlated with the changes in lipids due to fenofibrate treatment. The present study was therefore undertaken to examine the changes in DNA methylation among the participants of Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. A total of 443 individuals were studied for epigenome-wide changes in DNA methylation, assessed using the Illumina Infinium HumanMethylation450 array, before and after a 3-week daily treatment with 160 mg of fenofibrate. The association between the change in DNA methylation and changes in TG, HDLc, and low-density lipoprotein cholesterol (LDLc) were assessed using linear mixed models adjusted for age, sex, baseline lipids, and study center as fixed effects and family as a random effect. Changes in DNA methylation were not significantly associated with changes in TG, HDLc, or LDLc after 3 weeks of fenofibrate for any CpG. CpG changes in genes known to be involved in fenofibrate response, e.g., PPAR-α, APOA1, LPL, APOA5, APOC3, CETP, and APOB, also did not show evidence of association. In conclusion, changes in lipids in response to 3-week treatment with fenofibrate were not associated with changes in DNA methylation. Studies of longer duration may be required to detect treatment-induced changes in methylation.
Highlights
Fenofibrate is a peroxisome proliferator-activated receptor-α (PPAR-α) agonist which improves lipid profiles, by reducing triglycerides (TG) and increasing high density lipoprotein cholesterol (HDLc) (Schoonjans et al, 1996; Staels et al, 1998)
The increase in plasma HDLc depends on overexpression of APOA1 as well as down regulation of the apolipoprotein B (APOB) (Auwerx et al, 1996; Staels et al, 1997; Fruchart and Duriez, 2006; Aslibekyan et al, 2015) and cholesteryl ester transfer protein, plasma (CETP) genes
In previous GOLDN (Genetics of Lipid Lowering Drug and Diet Network) publications, common genetic polymorphisms were found to be associated with variation in fenofibrate response
Summary
Fenofibrate is a peroxisome proliferator-activated receptor-α (PPAR-α) agonist which improves lipid profiles, by reducing triglycerides (TG) and increasing high density lipoprotein cholesterol (HDLc) (Schoonjans et al, 1996; Staels et al, 1998). Findings included genes encoding the scavenger receptor class B, member 1 (SCARB1), a key component in the reverse cholesterol transport (Liu et al, 2008); APOA5, an important player in lipid metabolism and homeostasis (Lai et al, 2007); ATPbinding cassette, sub-family A (ABC1), member 1 (ABCA1), involved in cellular lipid efflux and HDL metabolism (Tsai et al, 2010); APOB, essential for transfer of TG and cholesteryl esters during lipoprotein metabolism (Wojczynski et al, 2010); and peroxisome proliferator-activated receptor alpha (PPARA), involved in the pharmacodynamic pathway (Frazier-Wood et al, 2013)
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